Compounds to treat alzheimer&#39;s disease

ABSTRACT

The present invention is directed toward substituted hydroxyethylene compounds of formula (XII)  
                 
 
     useful in treating Alzheimer&#39;s disease and other similar diseases.

CROSS—REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority of invention under 35 U.S.C.§119(e) from U.S. provisional application No. 60/191,528, filed Mar. 23,2000.

FIELD OF THE INVENTION

[0002] The present invention is compounds useful in treating Alzheimer'sdisease and other similar diseases.

BACKGROUND OF THE INVENTION

[0003] Alzheimer's disease (AD) is a progressive degenerative disease ofthe brain primarily associated with aging which results in loss ofmemory and orientation. As the disease progresses, motor, sensory andlinguistic abilities are also affected until there is global impairmentof multiple cognitive functions. These cognitive losses occur gradually,but typically lead to severe impairment and eventual death in the rangeof four to twelve years.

[0004] Alzheimer's disease is characterized by two major pathologicobservations in the brain: neurofibrillary tangles and amyloid (orneuritic) plaques, particularly in those regions involved with memoryand cognition (see, Selkoe D J, “Translating cell biology intotherapeutic advances in Alzheimer's disease,” Nature ( ENGLAND ) Jun.24, 1999, 399 (6738 Suppl) pA23-31). Smaller numbers of these lesions ina more restricted anatomical distribution are found in the brains ofmost aged humans who do not have clinical AD. Amyloid plaque andneurofibrillary tangles are comprised predominantly of an aggregate of apeptide fragment known as beta-amyloid peptide (Aβ).

[0005] Amyloidogenic plaques and vascular amyloid angiopathy alsocharacterize the brains of individuals with Trisomy 21 (Down's Syndrome)and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type(HCHWA-D). At present, a definitive diagnosis of AD usually requiresobserving the aforementioned lesions in the brain tissue of patients whohave died with the disease or, rarely, in small biopsied samples ofbrain tissue taken during an invasive neurosurgical procedure.

[0006] Neurofibrillary tangles are characterized as networks ofmicrotubules and microfilaments which were once structural supportsrunning symmetrically through the nerve cells transporting nutrients,but have degenerated into dysfunctional tangled masses. They can bedescribed histologically as non-membrane bound bundles containingpaired, helically wound filaments (PHF) that are approximately 10 nm inlength and located in the perinuclear cytoplasm of certain neurons.Major components of paired helical filaments are highly phosphorylatedtau proteins (PHF-tau) of 60 kDa, 64 kDa and 68 kDa. Tau belongs to thefamily of microtubule-associated proteins and plays a role in themicrotubule assembly and stabilization. In certain otherneurodegenerative disorders, including corticobasal degeneration (CBD),progressive supranuclear palsy (PSP) and Pick's disease,hyperphosphorylated tau proteins also accumulate in brain tissue inassociation with abnormal filaments. Recent research indicates that thepattern of hyperphosphorylation and the resulting ultrastructure of thehelical filaments are somewhat different in each type of disease.

[0007] At present there are no effective treatments for halting,preventing or reversing the progression of Alzheimer's disease; onlytreatments that palliate symptoms are thus far available. Therefore,there is an urgent need for pharmaceutical agents capable of slowing theprogression of Alzheimer's disease and/or preventing it in the firstplace.

OF GENERAL INTEREST

[0008] United States Patents:

[0009] 1. U.S. Pat. No. 5,733,882

[0010] 2. U.S. Pat. No. 4,880,781

[0011] 3. U.S. Pat. No. 5,663,200

[0012] 4. U.S. Pat. No. 5,807,891

[0013] 5. U.S. Pat. No. 5,935,976

[0014] 6. U.S. Pat. No. 4,668,770

[0015] 7. U.S. Pat. No. 6,013,658

[0016] 8. U.S. Pat. No. 5,162,538

[0017] International Patents and Patent Applications:

[0018] 1. WO 93/02057

[0019] 2. WO 93/17003

[0020] 3. EP 0320205

[0021] 4. WO 87/02986

[0022] 5. WO 89/01488

[0023] 6. WO 92/17490

[0024] 7. WO 89/00161

[0025] 8. GB 2203740

[0026] 9. EP 0337714

[0027] 10. DE 3721855

[0028] 11. EP 0209897

[0029] 12. EP 0264106

[0030] 13. WO 8704349

[0031] 14. JP 7-126286

[0032] 15. EP 0212903

[0033] 16. JP 297664

[0034] 17. EP 0372537

[0035] 18. WO 97/30072

[0036] 19. EP 0437729

[0037] Literature References

[0038] 1. Sakurai, M., et al., Chem. Pharm. Bull. (1993), 41, 8,1378-1386.

[0039] 2. Sakurai, M., et al., Tetrahedron Lett. (1993), 34, 37,5939-5942.

[0040] 3. Diederich, A. M., et al., Tetrahedron Lett. (1993), 34, 39,6169-6172.

SUMMARY OF INVENTION

[0041] This invention is directed to the novel compounds of formula 1that are useful in treating Alzheimer's disease and other similardiseases.

[0042] Disclosed are hydroxyethylene compounds of the formula (XII):

[0043] where R₁ is:

[0044] (I) C₁-C₆ alkyl,

[0045] (II) C₁-C₆ alkyl-S-alkyl

[0046] (III) C₁-C₆ alkyl-(C₂-C₆ alkenyl),

[0047] (IV) —(CH₂)₀₋₆-alkyl -(R_(1-aryl) where R)_(1-aryl is unsubstituted or substituted with:)

[0048] (A) C₁-C₆ alkyl,

[0049] (B) —CF₃,

[0050] (C) —F, Cl, —Br or —I,

[0051] (D) C₁-C₃ alkoxy,

[0052] (E) —O—CF₃,

[0053] (F) —NH₂,

[0054] (G) —OH, or

[0055] (H) —C≡N,

[0056] (V) —(CH₂)₀₋₆-alkyl -(R_(1-heteroatyl)) where R_(1-heteroaryl)is:

[0057] (A) pyridinyl,

[0058] (B) pyrimidinyl,

[0059] (C) quinolinyl,

[0060] (D) indenyl,

[0061] (E) indanyl,

[0062] (F) benzothiophenyl,

[0063] (G) indolyl,

[0064] (H) indolinyl,

[0065] (I) pyridazinyl,

[0066] (J) pyrazinyl,

[0067] (K) isoindolyl,

[0068] (L) isoquinolyl,

[0069] (M) quinazolinyl,

[0070] (N) quinoxalinyl,

[0071] (O) phthalazinyl,

[0072] (P) inidazolyl,

[0073] (Q) isoxazolyl,

[0074] (R) pyrazolyl,

[0075] (S) oxazolyl,

[0076] (T) thiazolyl,

[0077] (U) indolizinyl,

[0078] (V) indazolyl,

[0079] (W) benzothiazolyl,

[0080] (X) benzimidazolyl,

[0081] (Y) benzofuranyl,

[0082] (Z) furanyl,

[0083] (AA) thienyl,

[0084] (BB) pyrrolyl,

[0085] (CC) oxadiazolyl,

[0086] (DD) thiadiazolyl,

[0087] (EE) triazolyl,

[0088] (FF) tetrazolyl,

[0089] (GG) 1,4-benzodioxan

[0090] (HH) purinyl,

[0091] (II) oxazolopyridinyl,

[0092] (JJ) irnidazopyridinyl,

[0093] (KK) isothiazolyl,

[0094] (LL) naphthyridinyl,

[0095] (MM) cinnolinyl,

[0096] (NN) carbazolyl,

[0097] (OO) β-carbolinyl,

[0098] (PP) isochromanyl,

[0099] (QQ) chromanyl,

[0100] (RR) ifrazanyl,

[0101] (SS) tetrahydroisoquinoline,

[0102] (TT) isoindolinyl,

[0103] (UU) isobenzotetrahydrofiuranyl,

[0104] (VV) isobenzotetrahydrothienyl,

[0105] (WW) isobenzothiophenyl,

[0106] (XX) benzoxazolyl, or

[0107] (YY) pyridopyridinyl,

[0108] where the R_(1-heteroaryl) group is bonded to -alkyl- by any ringatom of the parent R_(N-heteroaryl) group substituted by hydrogen suchthat the new bond to the R_(1-heteroaryl) group replaces the hydrogenatom and its bond, where R_(1-heteroaryl) is unsubstituted orsubstituted with:

[0109] (1) C₁-C₃ alkyl,

[0110] (2) —CF₃,

[0111] (3) —F, Cl, —Br, or I,

[0112] (4) C₁-C₃ alkoxy,

[0113] (5) —O—CF₃,

[0114] (6) —NH₂,

[0115] (7) —OH, or

[0116] (8) —C≡N,

[0117] (VI) -(R_(1-heteroaryl)) where R_(1-heteroaryl) is as definedabove,

[0118] (VII) -C₁—C₅ alkyl-(R_(1-heterocycle)) where R_(1-heterocycle)is:

[0119] (A) morpholinyl,

[0120] (B) thiomorpholinyl,

[0121] (C) thiomorpholinyl S-oxide,

[0122] (D) thiomorpholinyl S,S-dioxide,

[0123] (E) piperazinyl,

[0124] (F) homopiperazinyl,

[0125] (G) pyrrolidinyl,

[0126] (H) pyrrolinyl,

[0127] (I) tetrahydropyranyl,

[0128] (J) piperidinyl,

[0129] (K) tetrahydrofuranyl, or

[0130] (L) tetrahydrothiophenyl,

[0131] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the RI heteroaryl group replaces the hydrogen atom and its bond,where R_(1-heterocycle) is unsubstituted or substituted with:

[0132] (1) ═O

[0133] (2) C₁-C₃ alkyl,

[0134] (3) —CF₃,

[0135] (4) —F, Cl, —Br or —I,

[0136] (5) C₁-C₃ alkoxy,

[0137] (6) —O—CF₃,

[0138] (7) —NH₂,

[0139] (8) —OH, or

[0140] (9) —CHN, or

[0141] (VIII) —R_(1-heterocycle with R) _(1-heterocycle) as definedabove;

[0142] where R₂ is:

[0143] (I) —H,

[0144] (II) alkyl, or

[0145] (III) —C₁-C₅ alkyl-R₂₋₁ where R₂₋₁ is cycloalkyl, R_(1-aryl) orR_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as definedabove,

[0146] where R_(N) is:

[0147] (I) R_(N-1)-X_(N)- where X_(N) is:

[0148] (A) —CO—,

[0149] (B) —SO₂—,

[0150] (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and are—H or C₁-C₄ alkyl,

[0151] (D) —CO—(CR′R″)₁₋₆-X_(N-1) where X_(N-1) is —O—, —S— or —NR′R″-and where R′ and R″ are as defined above, or

[0152] (E) a single bond;

[0153] where R_(N-1) is:

[0154] (A) R_(N-aryl) where R_(N-aryl) is unsubstituted or substitutedwith:

[0155] (1) C₁-C₆ alkyl,

[0156] (2) —F, —Cl, —Br, or —I,

[0157] (3) —OH,

[0158] (4) —NO₂,

[0159] (5) —CO—OH,

[0160] (6) —C≡N,

[0161] (7) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are:

[0162] (a) —H,

[0163] (b) —C₁-C₆ alkyl unsubstituted or substituted with

[0164] (i) —OH, or

[0165] (ii) —NH₂,

[0166] (c) —C₁-C₆ alkyl unsubstituted or substituted with —F, —Cl, —Br,or —I,

[0167] (d) —C₃-C₇ cycloalkyl,

[0168] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[0169] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[0170] (g) —C₁-C₆ alkenyl with one or two double bonds,

[0171] (h) —C₁-C₆ alkynyl with one or two triple bonds,

[0172] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0173] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[0174] (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above,

[0175] (8) —CO—(C₃-C₁₂ alkyl),

[0176] (9) —CO—(C₃-C₆ cycloalkyl),

[0177] (10) —CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove,

[0178] (11) —CO—R_(1-heteocycle) where R_(1-heterocycle) is as definedabove,

[0179] (12) —CO—RN₄ where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with C₁-C₃ alkyl,

[0180] (13) —CO—O—R_(N-5) where R_(N-5) is:

[0181] (a) alkyl, or

[0182] (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[0183] (14) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are asdefined above,

[0184] (15) —SO—(C₁-C₈ alkyl),

[0185] (16) —SO₂(C₃-C₁₂ alkyl),

[0186] (17) —NH—CO—O—RN₅ where R_(N-5) is as defined above,

[0187] (18) —NH—CO—N(C₁-C₃ alkyl)₂,

[0188] (19) —N—CS—N(C₁-C₃ alkyl)₂,

[0189] (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as definedabove,

[0190] (21) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can be the sameor different and are as defined above,

[0191] (22) —R_(N-4) where R_(N-4) is as defined above,

[0192] (23) —O—CO—(C₁-C₆ alkyl),

[0193] (24) —O—CO—N(C₁-C₃ alkyl)₂,

[0194] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[0195] (26) —O—(C₁-C₆ alkyl),

[0196] (27) —O—(C₂-C₅ alkyl)-COOH,

[0197] (28) —S—(C₁-C₆ alkyl),

[0198] (29) C₁-C₆ alkyl unsubstituted or substituted with halo,

[0199] (30) —O—(C₁-C₆ alkyl unsubstituted or substituted with halo), or

[0200] (31) —O—φ,

[0201] (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is:

[0202] (A) pyridinyl,

[0203] (B) pyrimidinyl,

[0204] (C) quinolinyl,

[0205] (D) indenyl,

[0206] (E) indanyl,

[0207] (F) benzothiophenyl,

[0208] (G) indolyl,

[0209] (H) indolinyl,

[0210] (I) pyridazinyl,

[0211] (J) pyrazinyl,

[0212] (K) isoindolyl,

[0213] (L) isoquinolyl,

[0214] (M) quinazolinyl,

[0215] (N) quinoxalinyl,

[0216] (O) phthalazinyl,

[0217] (P) imidazolyl,

[0218] (Q) isoxazolyl,

[0219] (R) pyrazolyl,

[0220] (S) oxazolyl,

[0221] (T) thiazolyl,

[0222] (U) indolizinyl,

[0223] (V) indazolyl,

[0224] (W) benzothiazolyl,

[0225] (X) benzimidazolyl,

[0226] (Y) benzofiranyl,

[0227] (Z) furanyl,

[0228] (AA) thienyl,

[0229] (BB) pyrrolyl,

[0230] (CC) oxadiazolyl,

[0231] (DD) thiadiazolyl,

[0232] (EE) triazolyl,

[0233] (FF) tetrazolyl,

[0234] (GG) 1,4-benzodioxan

[0235] (HH) purinyl,

[0236] (II) oxazolopyridinyl,

[0237] (JJ) imidazopyridinyl,

[0238] (KK) isothiazolyl,

[0239] (LL) naphthyridinyl,

[0240] (MM) cinnolinyl,

[0241] (NN) carbazolyl,

[0242] (OO) β-carbolinyl,

[0243] (PP) isochromanyl,

[0244] (QQ) chromanyl,

[0245] (RR) furazanyl,

[0246] (SS) tetrahydroisoquinoline,

[0247] (TT) isoindolinyl,

[0248] (UU) isobenzotetrahydrofuranyl,

[0249] (VV) isobenzotetrahydrothienyt,

[0250] (WW) isobenzothiophenyl,

[0251] (XX) benzoxazolyl, or

[0252] (YY) pyridopyridinyl,

[0253] where the R_(N-heteroaryl) group is bonded by any atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(N-heteroaryl) group replaces the hydrogen atom and itsbond, where _(N-heteroaryl) is unsubstituted or substituted with:

[0254] (1) C₁-C₆ alkyl,

[0255] (2) —F, —Cl, —Br, or —I,

[0256] (3) —OH,

[0257] (4) —NO₂,

[0258] (5) —CO—OH,

[0259] (6) —C≡N,

[0260] (7) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are:

[0261] (a) —H,

[0262] (b) —C₁-C₆ alkyl unsubstituted or substituted with:

[0263] (i) —OH, or

[0264] (ii) —NH₂,

[0265] (c) —C₁-C₆ alkyl substituted or substituted with —F, —Cl, —Br, or—I,

[0266] (d) —C₃-C₇ cycloalkyl,

[0267] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[0268] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[0269] (g) —C₁-C₆ alkenyl with one or two double bonds,

[0270] (h) —C₁-C₆ alkynyl with one or two triple bonds,

[0271] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0272] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[0273] (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above,

[0274] (8) —CO—(C₃-C₁₂ alkyl),

[0275] (9) —CO—(C₃-C₆ cycloalkyl),

[0276] (10) —CO—R_(1-heteroayl) where R_(1-heteroaryl) is as definedabove,

[0277] (11) —CO—R_(1-heterocycle) where R_(1-heterocyle) is as definedabove,

[0278] (12) —CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with C₁-C₃ alkyl,

[0279] (13) —CO—O—R_(N-5) where R_(N-5) is:

[0280] (a) C₁-C₆ alkyl, or

[0281] (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[0282] (14) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are as definedabove,

[0283] (15) —SO—(C₁-C₈ alkyl),

[0284] (16) —SO₂(C₃-C₁₂ alkyl),

[0285] (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,

[0286] (18) —NH—CO—N(C₁-C₃ alkyl)₂,

[0287] (19) —N—CS—N(C₁-C₃ alkyl)₂,

[0288] (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as definedabove,

[0289] (21) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) can be the same ordifferent and are as defined above,

[0290] (22) —R_(N-4) where R_(N-4) is as defined above,

[0291] (23) —O—CO—(C₁-C₆ alkyl),

[0292] (24) O—CO—N(C₁-C₃ alkyl)₂,

[0293] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[0294] (26) —O—(C₁-C₆ alkyl),

[0295] (27) —O—(C₂-C₅ alkyl)-COOH, or

[0296] (28) —S—(C₁-C₆ alkyl),

[0297] (C) —R_(N-aryl)-R_(N-aryl) where —R_(N-aryl) is as defined above,

[0298] (D) —R_(N-aryl)-R_(N-heteroaryl) where R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[0299] (E) —R_(N-heteroatyl)-R_(N-aryl) where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[0300] (F) —R_(N-heteroaryl)R_(N-heteroaryl) where R_(N-heteroaryl) isas defined above,

[0301] (G) —R_(N-aryl)-O—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[0302] (H) —R_(N-aryl)—S—R_(N-aryl) where —R_(N-ary) is as definedabove,

[0303] (I) —R_(N-heteroaryl)-O—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[0304] (J) —R_(N-heteroaryl)—S—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[0305] (K) —R_(N-aryl)—CO—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[0306] (L) —R_(N-aryl)—CO—R_(N-heteroaryl) where —R_(N-aryl) andR_(N-heteroaryl) are as defined above,

[0307] (M) —R_(N-aryl)—SO₂R_(N-aryl) where R_(N-aryl) is as definedabove,

[0308] (N) —R_(N-heteroaryl)—CO—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[0309] (O) —R_(N-heteroayl)—SO₂—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[0310] (P) —R_(N-aryl)-O—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[0311] (Q) —R_(N-aryl)—S—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[0312] (R) —R_(N-heteroaryl)-O—(C₁-C₈ alkyl)-φ where R_(N-heteroaryl) isas defined above, or

[0313] (S) —R_(N-heteroaryl)—S—(C₁-C₈ alkyl)-φ where R_(N-heteroaryl) isas defined above,

[0314] (II) —CO—(C₁-C₆ alkyl) where alkyl is unsubstituted orsubstituted with:

[0315] (A) —OH,

[0316] (B) —C₁-C₆ alkoxy,

[0317] (C) —C₁-C₆ thioalkoxy,

[0318] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[0319] (E) —CO—NR_(N-2) R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0320] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[0321] (G) —SO₂—(C₁-C₈ alkyl),

[0322] (H) —SO₂—NR_(N-2) R_(N-3)where R_(N-2) and R_(N-3) are the sameor different and are as defined above,

[0323] (I) —NH—CO—(C₁-C₆ alkyl),

[0324] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[0325] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0326] (L) —R_(N-4) where R_(N-4) is as defined above,

[0327] (M) —O—CO—(C₁-C₆ alkyl),

[0328] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) are the same ordifferent and are as defined above, or

[0329] (O) —O—(C₁-C₅ alkyl)-COOH,

[0330] (III) —CO—(C₁-C₃ alkyl)-O—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with:

[0331] (A) —OH,

[0332] (B) —C₁-C₆ alkoxy,

[0333] (C) —C₁-C₆ thioalkoxy,

[0334] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[0335] (E) —CO—NR_(N-2) R_(N-3) where R_(N-2) and R_(N-3) are the sameor different and are as defined above,

[0336] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[0337] (G) —SO₂—(C₁-C₈ alkyl),

[0338] (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the sameor different and are as defined above,

[0339] (I) —NH—CO—(C₁-C₆ alkyl),

[0340] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[0341] (K) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0342] (L) —R_(N-4) where R_(N-4) is as defined above,

[0343] (M) —O—CO—(C₁-C₆ alkyl),

[0344] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) are the same ordifferent and are as defined above, or

[0345] (O) —O—(C₁-C₅ alkyl)-COOH,

[0346] (IV) —CO—(C₁-C₃ alkyl)-S—(C₁-C₃ alkyl) where alkyl is:

[0347] (A) —OH,

[0348] (B) —C₁-C₆ alkoxy,

[0349] (C) —C₁-C₆ thioalkoxy,

[0350] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[0351] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0352] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[0353] (G) —SO₂—(C₁-C₈ alkyl),

[0354] (H) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0355] (I) —NH—CO—(C₁-C₆ alkyl),

[0356] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[0357] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0358] (L) —R_(N-4) where R_(N-4) is as defined above,

[0359] (M) —O—CO—(C₁-C₆ alkyl),

[0360] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) are the same ordifferent and are as defined above, or

[0361] (O) —O—(C₁-C₅ alkyl)-COOH,

[0362] (V)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂R_(N-aryl)/R_(N-heteroaryl)) whereR_(N-aryl) and R_(N-heteroaryl) are as defined above, where R_(N-10) isselected from the group consisting of:

[0363] (A) —H,

[0364] (B) C₁-C₆ alkyl,

[0365] (C) C₃-C₇ cycloalkyl,

[0366] (D) C₂-C₆ alkenyl with one double bond,

[0367] (E) C₂-C₆ alkynyl with one triple bond,

[0368] (F) R_(1-aryl) where R_(1-aryl) is as defined above, or

[0369] (G) R_(N-heteroaryl) where R_(N-heteroaryl) is as defined above;

[0370] where B is —O—, —NH—, or —N(C₁-C₆ alkyl)-;

[0371] where RC is:

[0372] (I) C₁-C₈ alkyl unsubstituted or substituted with —OH, —O—φ,halo, or (C₁-C₆ alkoxy unsubstituted or substituted with halo),

[0373] (II) —(CH₂)₀₋₃-alkyl-(C₃-C₇) cycloalkyl where cycloalkyl isunsubstituted or substituted with:

[0374] (A) C₁-C₃ alkyl unsubstituted or substituted with —F, —Cl, —Br,or —I,

[0375] (B) —CO—OH,

[0376] (C) —CO—O—(C₁-C₄ alkyl),

[0377] (D) —OH, or

[0378] (E) C₁-C₆ alkoxy,

[0379] (III) —(CH₂)₂₋₆—OH,

[0380] (IV) —(CR_(C-x)R_(c-y))₀₋₄—R_(C-aryl) where R_(C-x) and R_(C-y)are —H, C₁-C₄ alkyl and φ- and R_(C-aryl) is the same as R_(N-aryl),

[0381] (V) —(CH₂)₀₋₄—R_(C-heteroaryl) where R_(C-heteroaryl) is the sameas R_(N-heteroaryl)

[0382] (VI) —(CH₂)₀₋₄—R_(C-heterocycle) where R_(C-heterocycle) is:

[0383] (A) pyridinyl,

[0384] (B) pyrimidinyl,

[0385] (C) quinolinyl,

[0386] (D) indenyl,

[0387] (E) indanyl,

[0388] (F) benzothiophenyl,

[0389] (G) indolyl,

[0390] (H) indolinyl,

[0391] (I) pyridazinyl,

[0392] (J) pyrazinyl,

[0393] (K) isoindolyl,

[0394] (L) isoquinolyl,

[0395] (M) quinazolinyl,

[0396] (N) quinoxalinyl,

[0397] (O) phthalazinyl,

[0398] (P) isoxazolyl,

[0399] (Q) pyrazolyl,

[0400] (R) indolizinyl,

[0401] (S) indazolyl,

[0402] (T) benzothiazolyl,

[0403] (U) benzimidazolyl,

[0404] (V) benzofuranyl,

[0405] (W) furanyl,

[0406] (X) thienyl,

[0407] (Y) pyrrolyl,

[0408] (Z) oxadiazolyl,

[0409] (AA) thiadiazolyl,

[0410] (BB) triazolyl,

[0411] (CC) tetrazolyl,

[0412] (DD) 1,4-benzodioxan

[0413] (EE) purinyl,

[0414] (FF) oxazolopyridinyl,

[0415] (GG) imidazopyridinyl,

[0416] (HH) isothiazolyl,

[0417] (II) naphthyridinyl,

[0418] (JJ) cinnolinyl,

[0419] (KK) carbazolyl,

[0420] (LL) P-carbolinyl,

[0421] (MM) isochromanyl,

[0422] (NN) chromanyl,

[0423] (OO) furazanyl,

[0424] (PP) tetrahydroisoquinoline,

[0425] (QQ) isoindolinyl,

[0426] (RR) isobenzotetrahydrofuranyl,

[0427] (SS) isobenzotetrahydrothienyl,

[0428] (TT) isobenzothiophenyl,

[0429] (UU) benzoxazolyl, or

[0430] (VV) pyridopyridinyl,

[0431] (VII) —C(R_(C-1))(R_(C-2))—CO—NH—R_(C-3) where R_(C-1) andR_(C-2) are the same or different and are:

[0432] (A) —H,

[0433] (B) —C₁-C₆ alkyl,

[0434] (C) —(C₁-C₄ alkyl)-R_(C′-aryl) where R_(C′-aryl) is as definedfor R_(1-aryl),

[0435] (D) —(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is asdefined above,

[0436] (E) —(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle) isas defined above,

[0437] (F) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above,

[0438] (G) —R_(C-heterocycle) where R_(C-heterocycle) is as definedabove,

[0439] (H) —(CH₂)₁₋₄—OH,

[0440] (I) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C′-aryl) where Rc4 is —O—, —S—,—NH—, or —NR_(C-5)- where R_(C-5) is C₁-C₆ alkyl, and where R_(C′-aryl)is defined above,

[0441] (J) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C-heteroaryl) where R_(C-4) andR_(C-heteroaryl) are as defined above, or

[0442] (K) —R_(C′-aryl) where R_(C′-aryl) is as defined above,

[0443] and where R_(C-3) is:

[0444] (A) —H,

[0445] (B) —C₁-C₆ alkyl,

[0446] (C) —R_(C′-aryl) where R_(C′-aryl) is as defined above,

[0447] (D) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above,

[0448] (E) —R_(C-heterocycle) where R_(C-heterocycle) is as definedabove,

[0449] (F) —(C₁-C₄ alkyl)-R_(C′-aryl) where R_(C′-aryl) is as definedabove,

[0450] (G) —(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is asdefined above, or

[0451] (H) —(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle) isas defined above,

[0452] (VIII) —CH(φ)₂,

[0453] (IX) -cyclopentyl or -cyclohexyl ring fused to a phenyl orheteroaryl ring where heteroaryl is as defined above and phenyl andheteroaryl are unsubstituted or substituted with:

[0454] (A) C₁-C₃ alkyl,

[0455] (B) —CF₃,

[0456] (C) —F, Cl, —Br or —I,

[0457] (D) C₁-C₃ alkoxy,

[0458] (E) —OCF₃,

[0459] (F) —NH₂,

[0460] (G) —OH, or

[0461] (H) —C≡N,

[0462] (X) —CH₂—C≡CH;

[0463] (XI) —(CH₂)₀₋₁—CHR_(C-5)—(CH₂)₀₋₁φ where R_(C-5) is:

[0464] (A) —OH, or

[0465] (B)—CH₂—OH;

[0466] (XII) —CH(—φ)—CO—O(C₁-C₃ alkyl);

[0467] (XIII) —CH(—CH₂—OH)—CH(—OH)—(—NO₂;

[0468] (XIV) —(CH₂)₂—O—(CH₂)₂—OH;

[0469] (XV) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂;

[0470] (XVI) —(C₂-C₈) alkynyl; or

[0471] (XVII) —H; and pharmaceutically acceptable salts thereof.

[0472] Also disclosed are hydroxyethylene compounds of the formula (XII)

[0473] where R₁ is:

[0474] (I) C₁-C₆ alkyl, unsubstituted or substituted with one, two orthree C I-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —NH₂, —CN, —CF₃, or —N₃,

[0475] (II) —(CH₂)₁₋₂—S—CH₃,

[0476] (III) —CH₂—CH₂—S—CH₃,

[0477] (IV) —CH₂—(C₂-C₆ alkenyl) unsubstituted or substituted by one —F,

[0478] (V) —(CH₂)₀₋₃-(R_(1-aryl)) where R_(1-aryl) is phenyl,1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinylunsubstituted or substituted on the aryl ring with one or two of thefollowing substituents which can be the same or different:

[0479] (A) C₁-C₃ alkyl,

[0480] (B) —CF₃,

[0481] (C) —F, Cl, —Br and —I,

[0482] (D) C₁-C₃ alkoxy,

[0483] (E) —O—CF₃,

[0484] (F) —NH₂,

[0485] (G) —OH, or

[0486] (H) —C—N,

[0487] (VI) —(CH₂)_(n1)—(R_(1-heteroaryl)) where n₁ is 0, 1, 2, or 3 andR_(1-heteroaryl) is:

[0488] (A) pyridinyl,

[0489] (B) pyrimidinyl,

[0490] (C) quinolinyl,

[0491] (D) indenyl,

[0492] (E) indanyl,

[0493] (F) benzothiophenyl,

[0494] (G) indolyl,

[0495] (H) indolinyl,

[0496] (I) pyridazinyl,

[0497] (J) pyrazinyl,

[0498] (K) isoindolyl,

[0499] (L) isoquinolyl,

[0500] (M) quinazolinyl,

[0501] (N) quinoxalinyl,

[0502] (O) phthalazinyl,

[0503] (P) imidazolyl,

[0504] (Q) isoxazolyl,

[0505] (R) pyrazolyl,

[0506] (S) oxazolyl,

[0507] (T) thiazolyl,

[0508] (U) indolizinyl,

[0509] (V) indazolyl,

[0510] (W) benzothiazolyl,

[0511] (X) benzimidazolyl,

[0512] (Y) benzofuranyl,

[0513] (Z) furanyl,

[0514] (AA) thienyl,

[0515] (BB) pyrrolyl,

[0516] (CC) oxadiazolyl,

[0517] (DD) thiadiazolyl,

[0518] (EE) triazolyl,

[0519] (FF) tetrazolyl,

[0520] (GG) 1,4-benzodioxan

[0521] (HH) purinyl,

[0522] (II) oxazolopyridinyl,

[0523] (JJ) imidazopyridinyl,

[0524] (KK) isothiazolyl,

[0525] (LL) naphthyridinyl,

[0526] (MM) cinnolinyl,

[0527] (NN) carbazolyl,

[0528] (OO) P-carbolinyl,

[0529] (PP) isochromanyl,

[0530] (QQ) chromanyl,

[0531] (RR) furazanyl,

[0532] (SS) tetrahydroisoquinoline,

[0533] (TT) isoindolinyl,

[0534] (UU) isobenzotetrahydrofuranyl,

[0535] (VV) isobenzotetrahydrothienyl,

[0536] (WW) isobenzothiophenyl,

[0537] (XX) benzoxazolyl, or

[0538] (YY) pyridopyridinyl,

[0539] where the R_(1-heteroaryl) group is bonded to —(CH₂)₀₋₃— by anyring atom of the parent R_(N-heteroaryl) group substituted by hydrogensuch that the new bond to the R_(1-heteroaryl) group replaces thehydrogen atom and its bond, where heteroaryl is unsubstituted orsubstituted with one or two:

[0540] (1) C₁-C₃ alkyl,

[0541] (2) —CF₃,

[0542] (3) —F, Cl, —Br, or —I,

[0543] (4) C₁-C₃ alkoxy,

[0544] (5) —0—CF₃,

[0545] (6) —NH₂,

[0546] (7) —OH, or

[0547] (8) —C—N,

[0548] with the proviso that when n₁ is zero R_(1-heteroaryl) is notbonded to the carbon chain by nitrogen, or

[0549] (VII) —(CH₂)_(n1)-(R_(1-heterocycle)) where n₁ is as definedabove and R_(1-heterocycle) is:

[0550] (A) morpholinyl,

[0551] (B) thiomorpholinyl,

[0552] (C) thiomorpholinyl S-oxide,

[0553] (D) thiomorpholinyl S,S-dioxide,

[0554] (E) piperazinyl,

[0555] (F) homopiperazinyl,

[0556] (G) pyrrolidinyl,

[0557] (H) pyrrolinyl,

[0558] (I) tetrahydropyranyl,

[0559] (J) piperidinyl,

[0560] (K) tetrahydrofuranyl, or

[0561] (L) tetrahydrothiophenyl,

[0562] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heteroaryl) group replaces the hydrogen atom and itsbond, where heterocycle is unsubstituted or substituted with one or two:

[0563] (1) ═O,

[0564] (2) C₁-C₃ alkyl,

[0565] (3) CF₃,

[0566] (4) —F, Cl, —Br and —I,

[0567] (5) C₁-C₃ alkoxy,

[0568] (6) —O—CF₃,

[0569] (7) —NH₂,

[0570] (8) —OH, or

[0571] (9) —C≡N,

[0572] with the proviso that when n₁ is zeroR_(1-heterocycle is not bonded to the carbon chain by nitrogen;)

[0573] where R₂ is:

[0574] (I) —H,

[0575] (II) C₁-C₆ alkyl, or

[0576] (III) —(CH₂)₀₋₄—R₂ ₁ where R₂ ₁ is (C₃-C₆)cycloalkyl, R_(1-aryl)or R-_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are asdefined above,

[0577] where R_(N) is:

[0578] (I) R_(N-1)-X_(N)- where X_(N) is:

[0579] (A)—CO—,

[0580] (B) —SO₂—,

[0581] (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and are—H or C₁-C₄ alkyl,

[0582] (D) —CO—(CR′R″)₁₋₆-X_(N-1) where X_(N-1) is -O—, —S—and —NR′R″-and where R′ and R″ are as defined above,

[0583] (E) a single bond;

[0584] where R_(N-1) is:

[0585] (A) R_(N-aryl) where R_(N-aryl) is phenyl, 1-naphthyl and2-naphthyl unsubstituted or substituted with one, two, three or four ofthe following substituents which can be the same or different and are:

[0586] (1) C₁-C₆ alkyl,

[0587] (2) —F, —Cl, —Br, or —I,

[0588] (3) —OH,

[0589] (4) —NO₂,

[0590] (5)—CO—OH,

[0591] (6) —C≡N,

[0592] (7) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are:

[0593] (a) —H,

[0594] (b) —C₁-C₆ alkyl unsubstituted or substituted with one

[0595] (i) —OH, or

[0596] (ii) —NH₂,

[0597] (c) —C₁-C₆ alkyl unsubstituted or substituted with one to three—F, —Cl, —Br, or —I,

[0598] (d) —C₃-C₇ cycloalkyl,

[0599] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[0600] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[0601] (g) —C₁-C₆ alkenyl with one or two double bonds,

[0602] (h) —C₁-C₆ alkynyl with one or two triple bonds,

[0603] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0604] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[0605] (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above,

[0606] (8) —CO—(C₃-C₁₂ alkyl),

[0607] (9) —CO—(C₃-C₆ cycloalkyl),

[0608] (10) —CO—R_(1-heteroaryl) where R_(1-heteroaryl), is as definedabove,

[0609] (11) —CO—R_(1-heterocycle where R) _(1-heterocycle) is as definedabove,

[0610] (12) —CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with one or two C₁-C₃ alkyl,

[0611] (13) —CO—O—R_(N-5) where R_(N-5) is:

[0612] (a) C₁-C₆ alkyl, or

[0613] (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[0614] (14) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are as definedabove,

[0615] (15) —SO—(C₁-C₈ alkyl),

[0616] (16) —SO₂(C₃-C₁₂ alkyl),

[0617] (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,

[0618] (18) —NH—CO—N(C₁-C₃ alkyl)₂,

[0619] (19) —N—CS—N(C₁C₃ alkyl)₂,

[0620] (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as definedabove,

[0621] (21) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) can be the same ordifferent and are as defined above,

[0622] (22) —R_(N-4) where R_(N-4) is as defined above,

[0623] (23) —O—CO—(C₁-C₆ alkyl),

[0624] (24) —O—CO—N(C₁-C₃ alkyl)₂,

[0625] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[0626] (26) —O—(C₁-C₆ alkyl),

[0627] (27) —O—(C₂-C₅ alkyl)-COOH,

[0628] (28) —S—(C₁-C₆ alkyl),

[0629] (29) C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3, 4, or5 —F,

[0630] (30) —O—(C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3,4, or 5 —F, or

[0631] (3 1) —O-φ,

[0632] (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is:

[0633] (A) pyridinyl,

[0634] (B) pyrimidinyl,

[0635] (C) quinolinyl,

[0636] (D) indenyl,

[0637] (E) indanyl,

[0638] (F) benzothiophenyl,

[0639] (G) indolyl,

[0640] (H) indolinyl,

[0641] (I) pyridazinyl,

[0642] (J) pyrazinyl,

[0643] (K) isoindolyl,

[0644] (L) isoquinolyl,

[0645] (M) quinazolinyl,

[0646] (N) quinoxalinyl,

[0647] (O) phthalazinyl,

[0648] (P) imidazolyl,

[0649] (Q) isoxazolyl,

[0650] (R) pyrazolyl,

[0651] (S) oxazolyl,

[0652] (T) thiazolyl,

[0653] (U) indolizinyl,

[0654] (V) indazolyl,

[0655] (W) benzothiazolyl,

[0656] (X) benzimidazolyl,

[0657] (Y) benzofuranyl,

[0658] (Z) furanyl,

[0659] (AA) thienyl,

[0660] (BB) pyrrolyl,

[0661] (CC) oxadiazolyl,

[0662] (DD) thiadiazolyl,

[0663] (EE) triazolyl,

[0664] (FF) tetrazolyl,

[0665] (GG) 1,4-benzodioxan

[0666] (HH) purinyl,

[0667] (II) oxazolopyridinyl,

[0668] (JJ) imidazopyridinyl,

[0669] (KK) isothiazolyl,

[0670] (LL) naphthyridinyl,

[0671] (MM) cinnolinyl,

[0672] (NN) carbazolyl,

[0673] (OO) β-carbolinyl,

[0674] (PP) isochromanyl,

[0675] (QQ) chromanyl,

[0676] (RR) furazanyl,

[0677] (SS) tetrahydroisoquinoline,

[0678] (TT) isoindolinyl,

[0679] (UU) isobenzotetrahydrofuranyl,

[0680] (VV) isobenzotetrahydrothienyl,

[0681] (WW) isobenzothiophenyl,

[0682] (XX) benzoxazolyl, or

[0683] (YY) pyridopyridinyl,

[0684] where the R_(N-heteroaryl) group is bonded by any atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(N-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is unsubstituted or substituted with one or two:

[0685] (1) C₁-C₆ alkyl,

[0686] (2) —F, —Cl, —Br, or —I,

[0687] (3) —OH,

[0688] (4) —NO₂,

[0689] (5) —CO—OH,

[0690] (6) —C≡N,

[0691] (7) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are:

[0692] (a) —H,

[0693] (b) —C₁-C₆ alkyl unsubstituted or substituted with one

[0694] (i) —OH, or

[0695] (ii) —NH₂,

[0696] (c) —C₁-C₆ alkyl unsubstituted or substituted with 1, 2, or 3 —F,—Cl, —Br, or —I,

[0697] (d) —C₃-C₇ cycloalkyl,

[0698] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[0699] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[0700] (g) —C₁-C₆ alkenyl with one or two double bonds,

[0701] (h) —C₁-C₆ alkynyl with one or two triple bonds,

[0702] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[0703] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[0704] (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above,

[0705] (8) —CO—(C₃-C₁₂ alkyl),

[0706] (9) —CO—(C₃-C₆ cycloalkyl),

[0707] (10) —CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove,

[0708] (11) —CO—R_(1-heterocycle) where R_(1-heterocycle) is as definedabove,

[0709] (12) —CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with one or two C₁-C₃ alkyl,

[0710] (13) —CO—O—R_(N-5) where R_(N-5) is:

[0711] (a) C₁-C₆ alkyl, or

[0712] (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[0713] (14) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are as definedabove,

[0714] (15) —SO—(C₁-C₈ alkyl),

[0715] (16) —SO₂(C₃-C₁₂ alkyl),

[0716] (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,

[0717] (18) —NH—CO—N(C₁-C₃ alkyl)₂,

[0718] (19) —N—CS—N(C₁-C₃ alkyl)₂,

[0719] (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as definedabove,

[0720] (21) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) can be the same ordifferent and are as defined above,

[0721] (22) —R_(N-4) where R_(N-4) is as defined above,

[0722] (23) —O—CO—(C₁-C₆ alkyl),

[0723] (24) —O—CO—N(C₁-C₃ alkyl)₂,

[0724] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[0725] (26) —O—(C₁-C₆ alkyl),

[0726] (27) —O—(C₂-C₅ alkyl)-COOH, or

[0727] (28) —S—(C₁-C₆ alkyl),

[0728] (C) —R_(N-aryl)-R_(N-aryl) where —R_(N-aryl) is as defined above,

[0729] (D) —R_(N-aryl)-R_(N-heteroaryl) where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[0730] (E) —R_(N-heteroaryl)-R_(N-aryl) where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[0731] (F) —R_(N-heteroaryl)-R_(N-heteroaryl) where R_(N-heteroaryl) isas defined above,

[0732] (G) —R_(N-aryl)-O-R_(N-aryl) where —R_(N-aryl) is as definedabove,

[0733] (H) —R_(N-aryl)-S—R-N_(aryl) where —R_(N-aryl) is as definedabove,

[0734] (I) —R_(N-heterearyl)-O-R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[0735] (J) —R_(N-heteroaryl)—S-R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[0736] (K) —R_(N-aryl)—CO-R_(Naryl) where —R_(N-aryl)is as definedabove,

[0737] (L) —R_(N-aryl)—CO-R_(N-heteroaryl) where —R_(N-aryl) andR_(N-heteroaryl) are as defined above,

[0738] (M) —R_(N-aryl)—SO₂—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[0739] (N) —R_(N-heteroaryl)—CO-R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[0740] (O) —R_(N-heteroaryl)—SO₂—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[0741] (P) —R_(N-aryl)-O—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[0742] (Q) —R_(N-aryl)—S—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[0743] (R) —R_(N-heteroaryl)-O—(C₁-C₈ alkyl)-φ where R_(N-heteroaryl) isas defined above, or

[0744] (S) —R_(N-heteroaryl)—S—(C₁-C₈ alkyl)-φ where R_(N-heteroaryl) isas defined above,

[0745] (II) A—X_(N)- where X_(N) is —CO—, wherein A is

[0746] (A) —T-E—(Q)_(m′),

[0747] (1) where —T is

[0748] where

[0749] (a) x=1 when y=1 and x=2 when y=0,

[0750] (b) m is 0, 1, 2 or 3,

[0751] (c) the values of x and y vary independently on each carbon whenm is 2 and 3, and

[0752] (d) R′″ varies independently on each carbon and is H, (C₁-C₂)alkyl, phenyl, or phenyl(C₁-C₃)alkyl;

[0753] (2) -E is

[0754] (a) C₁-C₅ alkyl, but only if m′ does not equal 0,

[0755] (b) methylthioxy(C₂-C₄)alkyl,

[0756] (c) an aryl group having 5 to 7 atoms when monocyclic or having 8to 12 atoms when fused,

[0757] (d) a heterocyclic group having 5 to 7 atoms when monocyclic orhaving 8 to 12 atoms when fused,

[0758] (e) a mono or fused ring cycloalkyl group having 5 to 10 carbonatoms,

[0759] (f) biphenyl,

[0760] (g) diphenyl ether,

[0761] (h) diphenylketone,

[0762] (i) phenyl(C₁-C₈)alkyloxyphenyl, or

[0763] (j) C₁-C₆ alkoxy;

[0764] (3) —Q is

[0765] (a) C₁-C₃ alkyl,

[0766] (b) C₁-C₃ alkoxy,

[0767] (c) C₁-C₃ alkylthioxy,

[0768] (d) C₁-C₆ alkylacylamino,

[0769] (e) C₁-C₆ alkylacyloxy,

[0770] (f) amido (including primary, C₁-C₆ alkyl and phenyl secondaryand tertiary amino moieties),

[0771] (g) C₁-C₆ alkylamino

[0772] (h) phenylamino,

[0773] (i) carbamyl (including C₁-C₆ alkyl and phenyl amides andesters),

[0774] (j) carboxyl (including C₁-C₆ alkyl and phenyl esters),

[0775] (k) carboxy(C₂-C₅)alkoxy,

[0776] (l) carboxy(C₂-C₅)alkylthioxy,

[0777] (m) heterocyclylacyl,

[0778] (n) heteroarylacyl, or

[0779] (o) hydroxyl;

[0780] (4) m′ is 0, 1, 2 or3;

[0781] (B) -E(Q)_(m″) wherein E and —Q are as defined as above and m″ is0, 1, 2, or 3;

[0782] (C) —T-E wherein -E and —Q are as defined as above; or

[0783] (D) -E wherein -E is as defined as above;

[0784] (III) CO—(C₁-C₆ alkyl) where alkyl is unsubstituted orsubstituted with one or two:

[0785] (A) —OH,

[0786] (B) —C₁-C₆ alkoxy,

[0787] (C) —C₁-C₆ thioalkoxy,

[0788] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[0789] (E) —CO—NR_(N-2) R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0790] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[0791] (G) —SO₂-(C₁-C₈ alkyl),

[0792] (H) —SO₂—NR_(N-2) R_(N-3)where R_(N-2) and R_(N-3) are the sameor different and are as defined above,

[0793] (I) —NH—CO—(C₁-C₆ alkyl),

[0794] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[0795] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0796] (L) —R_(N-4) where R_(N-4) is as defined above,

[0797] (M) —O—CO—(C₁-C₆ alkyl),

[0798] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) is the same ordifferent and are as defined above, or

[0799] (O) —O—(C₁-C₅ alkyl)-COOH,

[0800] (IV) —CO—(C₁-C₃ alkyl)-O—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with one or two

[0801] (A) —OH,

[0802] (B) —C₁-C₆ alkoxy,

[0803] (C) —C₁-C₆ thioalkoxy,

[0804] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[0805] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0806] (F) —CO—RN₄ where R_(N-4) is as defined above,

[0807] (G) —SO₂—(C₁-C₈ alkyl),

[0808] (H) —SO2—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0809] (I) —NH—CO—(C₁-C₆ alkyl),

[0810] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[0811] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0812] (L) —R_(N-4) where R_(N-4) is as defined above,

[0813] (M) —O—CO—(C₁-C₆ alkyl),

[0814] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) are the same ordifferent and are as defined above, or

[0815] (O) —O—(C₁-C₅ alkyl)-COOH,

[0816] (V) —CO—(C₁-C₃ alkyl)-S—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with one or two

[0817] (A) —OH,

[0818] (B) —C₁-C₆ alkoxy,

[0819] (C) —C₁-C₆ thioalkoxy,

[0820] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[0821] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0822] (F) —CO—RN—₄ where R_(N-4) is as defined above,

[0823] (G) —SO₂—(C₁-C₈ alkyl),

[0824] (H) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0825] (I) —NH—CO—(C₁-C₆ alkyl),

[0826] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[0827] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[0828] (L) —R_(N-4) where R_(N-4) is as defined above,

[0829] (M) —O—CO—(C₁-C₆ alkyl),

[0830] (N) —O—CO—NRN8R_(N-8) where the R_(N-8) are the same or differentand are as defined above, or

[0831] (O) —O—(C₁-C₅ alkyl)-COOH,

[0832] (VI)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl)) whereR_(N-aryl) and R_(N-heteroaryl) are as defined above, where R_(N-10) is:

[0833] (A) —H,

[0834] (B) C₁-C₆ alkyl,

[0835] (C) C₃-C₇ cycloalkyl,

[0836] (D) C₂-C₆ alkenyl with one double bond,

[0837] (E) C₂-C₆ alkynyl with one triple bond,

[0838] (F) R_(1-aryl) where R_(1-aryl) is as defined above, or

[0839] (G) R_(N-heteroatyl) where R_(N-heteroaryl) is as defined above;

[0840] where B is —O—, —NH—, or —N(C₁-C₆ alkyl)-;

[0841] where R_(C) is:

[0842] (I) —(C₁-C₁₀)alkyl-K₁₋₃ in which:

[0843] (A) the alkyl chain is unsubstituted or substituted with one —OH,

[0844] (B) the alkyl chain is unsubstituted or substituted with oneC₁-C₆ alkoxy unsubstituted or substituted with 1-5 —F,

[0845] (C) the alkyl chain is unsubstituted or substituted with one—O-φ,

[0846] (D) the alkyl chain is unsubstituted or substituted with 1-5 —F,

[0847] (E) the alkyl chain is unsubstituted or substituted with acombination of up to three atoms of oxygen and sulfur each such atomreplacing one carbon,

[0848] (F) each K is:

[0849] (1) H,

[0850] (2) C₁-C₃ alkyl,

[0851] (3) C₁-C₃ alkoxy,

[0852] (4) C₁-C₃ alkylthioxy,

[0853] (5) C₁-C₆ alkylacylamino,

[0854] (6) C₁-C₆ alkylacyloxy,

[0855] (7) amido

[0856] (8) C₁-C₆ alkylamino

[0857] (9) phenylamino,

[0858] (10) carbamyl

[0859] (11) carboxyl

[0860] (12) carboxy(C₂-C₅)alkoxy,

[0861] (13) carboxy(C₂-C₅)alkylthioxy,

[0862] (14) heterocyclylacyl,

[0863] (15) heteroarylacyl,

[0864] (16) amino unsubstituted or substituted with C₁-C₆ alkyl,

[0865] (17) hydroxyl, or

[0866] (18) carboxyl methyl ester;

[0867] (II)-(CH₂)₀₋₃-J-[(-(CH₂)₀₋₃-K]₁₋₃ where K is as defined above andJ is:

[0868] (A) a 5 to 7 atom monocyclic aryl group,

[0869] (B) a 8 to 12 atom multicyclic aryl group,

[0870] (C) a 5 to 7 atom heterocyclic group,

[0871] (D) a 8 to 12 atom multicyclic heterocyclic group, or

[0872] (E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group;

[0873] (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkyl where cycloalkyl can beunsubstituted or substituted with one, two or three

[0874] (A) C₁-C₃ alkyl unsubstituted or substituted with 1, 2, 3, or 4—F, —Cl, —Br, or —I,

[0875] (B) —CO—OH,

[0876] (C) —CO—O—(C₁-C₄ alkyl),

[0877] (D) —OH, or

[0878] (E) C₁-C₆ alkoxy,

[0879] (IV) —(CH₂)₂-₆—OH,

[0880] (V) -(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl) where R_(C−x) and R_(C−y)are —H, C₁-C₄ alkyl and φ- and R_(C-aryl) is the same as R_(N-aryl),

[0881] (VI) (CH₂)₀₋₄—R_(C-heteroaryl) where R_(C-heteroaryl) is:

[0882] (A) pyridinyl,

[0883] (B) pyrimidinyl,

[0884] (C) quinolinyl,

[0885] (D) indenyl,

[0886] (E) indanyl,

[0887] (F) benzothiophenyl,

[0888] (G) indolyl,

[0889] (H) indolinyl,

[0890] (I) pyridazinyl,

[0891] (J) pyrazinyl,

[0892] (K) isoindolyl,

[0893] (L) isoquinolyl,

[0894] (M) quinazolinyl,

[0895] (N) quinoxalinyl,

[0896] (O) phthalazinyl,

[0897] (P) isoxazolyl,

[0898] (Q) pyrazolyl,

[0899] (R) indolizinyl,

[0900] (S) indazolyl,

[0901] (T) benzothiazolyl,

[0902] (U) benzimidazolyl,

[0903] (V) benzofuranyl,

[0904] (W) furanyl,

[0905] (X) thienyl,

[0906] (Y) pyrrolyl,

[0907] (Z) oxadiazolyl,

[0908] (AA) thiadiazolyl,

[0909] (BB) triazolyl,

[0910] (CC) tetrazolyl,

[0911] (DD) 1,4-benzodioxan

[0912] (EE) purinyl,

[0913] (FF) oxazolopyridinyl,

[0914] (GG) imidazopyridinyl,

[0915] (HH) isothiazolyl,

[0916] (II) naphthyridinyl,

[0917] (JJ) cinnolinyl,

[0918] (KK) carbazolyl,

[0919] (LL) β-carbolinyl,

[0920] (MM) isochromanyl,

[0921] (NN) chromanyl,

[0922] (OO) furazanyl,

[0923] (PP) tetrahydroisoquinoline,

[0924] (QQ) isoindolinyl,

[0925] (RR) isobenzotetrahydrofuranyl,

[0926] (SS) isobenzotetrahydrothienyl,

[0927] (TT) isobenzothiophenyl,

[0928] (UU) benzoxazolyl, or

[0929] (VV) pyridopyridinyl,

[0930] (VII) —(CH₂)₀₋₄—R_(C-heterocycle) where R_(C-heterocycle) is thesame as R_(1-heterocycle,)

[0931] (VIII) -C(R_(C−1))(R_(C−2))—CO—NH—RC₃ where RC-i and RC-₂ are thesame or different and are:

[0932] (A) —H,

[0933] (B) —C₁-C₆ alkyl,

[0934] (C) —(C₁-C₄ alkyl)-R_(C-aryl) where R_(C-aryl) is as definedabove for R_(1-aryl),

[0935] (D) —(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is asdefined above,

[0936] (E) —(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle) isas defined above,

[0937] (F) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above,

[0938] (G) —R_(C-heterocycle) where R_(C-heterocycle) is as definedabove,

[0939] (H) —(CH₂)₁₋₄—OH,

[0940] (I) —(CH₂)₁₋₄—R_(C−4)—(CH₂)₁₋₄—R_(C′-aryl) where R_(C−4) is —O—,—S—, —NH—or —NHR_(C−5)- where R_(C−5) is C₁-C₆ alkyl, and whereR_(C′-aryl) is as defined above,

[0941] (J) —(CH₂)₁₋₄—R_(C−4)-(CH₂)₁₋₄—R_(C-heteroaryl) where R_(C−4) andR_(C-heteroaryl) are as defined above, or

[0942] (K) —R_(C′-aryl) where R_(C′-aryl) is as defined above,

[0943] and where R_(C−3) is:

[0944] (A) —H,

[0945] (B) —C₁-C₆ alkyl,

[0946] (C) —R_(C′-aryl) where R_(C′-aryl) is as defined above,

[0947] (D) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above,

[0948] (E) —R_(C-heterocycle) where R_(C-heterocycle) is as definedabove,

[0949] (F) -(C₁-C₄ alkyl)-R_(C′-aryl) where R_(C′-aryl) is as definedabove,

[0950] (G) -(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is asdefined above, or

[0951] (H) -(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle) isas defined above,

[0952] (IX) —CH(φ)₂,

[0953] (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl orheteroaryl ring where heteroaryl is as defined above and phenyl andheteroaryl are unsubstituted or substituted with one, two or three:

[0954] (A) C₁-C₃ alkyl,

[0955] (B) —CF₃,

[0956] (C) —F, Cl, —Br and —I,

[0957] (D) C₁-C₃ alkoxy,

[0958] (E) —OCF₃,

[0959] (F) —NH₂,

[0960] (G) —OH, or

[0961] (H) —C≡N,

[0962] (XI) —CH₂—C≡—CH;

[0963] (XII) —(CH₂)₀₋₁-CHRE_(C−5)—(CH₂)₀₋₁-φ where R_(C−5) is:

[0964] (A) —OH, or

[0965] (B)—CH₂—OH;

[0966] (XIII) —CH(-φ)—CO—O(C₁-C₃ alkyl);

[0967] (XIV) —CH(—CH₂—OH)—CH(—OH)-φ—NO₂;

[0968] (XV) —(CH₂)₂—O—(CH₂)₂—OH;

[0969] (XVI) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂;

[0970] (XVII) -(C₂-C₈) alkynyl; or

[0971] (XVIII) —H; or a pharmaceutically acceptable salt thereof.

[0972] Additionally disclosed are compounds of the formula

[0973] where R₁ is:

[0974] (V) —CH₂-phenyl, where phenyl is substituted with two —F in the3- and 5-positions giving 3, 5-difluorophenyl, or

[0975] (VI) —(CH₂)_(n1)-(R_(1-heteroaryl)), where n1 andR_(1-heteroaryl) are as defined above; and

[0976] PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl,trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl,iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-l-enyloxycarbonyl,5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobomyloxycarbonyl, -phenyl-C(═N)—H, or 1-piperidyloxycarbonyl.

[0977] Additionally disclosed are epoxide compounds of the formula

[0978] where R₁ is:

[0979] (A) —CH₂-φ where -φ is substituted with two —F,

[0980] (B) —(CH₂)_(n1)—R_(heteroaryl) where n₁ is 0, 1, 2, or 3 andR_(1-heteroaryl) is:

[0981] (A) pyridinyl,

[0982] (B) pyrimidinyl,

[0983] (C) quinolinyl,

[0984] (D) indenyl,

[0985] (E) indanyl,

[0986] (F) benzothiophenyl,

[0987] (G) indolyl,

[0988] (H) indolinyl,

[0989] (I) pyridazinyl,

[0990] (J) pyrazinyl,

[0991] (K) isoindolyl,

[0992] (L) isoquinolyl,

[0993] (M) quinazolinyl,

[0994] (N) quinoxalinyl,

[0995] (O) phthalazinyl,

[0996] (P) imidazolyl,

[0997] (Q) isoxazolyl,

[0998] (R) pyrazolyl,

[0999] (S) oxazolyl,

[1000] (T) thiazolyl,

[1001] (U) indolizinyl,

[1002] (V) indazolyl,

[1003] (W) benzothiazolyl,

[1004] (X) benzimidazolyl,

[1005] (Y) benzofuranyl,

[1006] (Z) fuiranyl,

[1007] (AA) thienyl,

[1008] (BB) pyrrolyl,

[1009] (CC) oxadiazolyl,

[1010] (DD) thiadiazolyl,

[1011] (EE) triazolyl,

[1012] (FF) tetrazolyl,

[1013] (GG) 1,4-benzodioxan

[1014] (HH) purinyl,

[1015] (II) oxazolopyridinyl,

[1016] (JJ) imidazopyridinyl,

[1017] (KK) isothiazolyl,

[1018] (LL) naphthyridinyl,

[1019] (MM) cinnolinyl,

[1020] (NN) carbazolyl,

[1021] (OO) β-carbolinyl,

[1022] (PP) isochromanyl,

[1023] (QQ) chromanyl,

[1024] (RR) farazanyl,

[1025] (SS) tetrahydroisoquinoline,

[1026] (TT) isoindolinyl,

[1027] (UU) isobenzotetrahydrofuranyl,

[1028] (VV) isobenzotetrahydrothienyl,

[1029] (WW) isobenzothiophenyl,

[1030] (XX) benzoxazolyl, or

[1031] (YY) pyridopyridinyl,

[1032] (C)—(CH₂)_(n1)—R_(1-heterocycle) where n₁ is 0, 1, 2, or 3 andR_(1-heterocycle) is:

[1033] (A) morpholinyl,

[1034] (B) thiomorpholinyl,

[1035] (C) thiomorpholinyl S-oxide,

[1036] (D) thiomorpholinyl S,S-dioxide,

[1037] (E) piperazinyl,

[1038] (F) homopiperazinyl,

[1039] (G) pyrrolidinyl,

[1040] (H) pyrrolinyl,

[1041] (I) tetrahydropyranyl,

[1042] (J) piperidinyl,

[1043] (K) tetrahydrofuranyl, or

[1044] (L) tetrahydrothiophenyl, and

[1045] PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, fonnyl,trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl,iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-l-enyloxycarbonyl,5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobornyloxycarbonyl, -phenyl-C(═N)—H, or 1-piperidyloxycarbonyl.

[1046] Additionally disclosed are compounds of the formula

[1047] where R₁ is:

[1048] (V) —CH₂-phenyl, where phenyl is substituted with two —F in the3- and 5-positions giving 3, 5-difluorophenyl, or

[1049] (VI) (CH₂)_(n1)-(R_(1-heteroaryl)), where n1 and R_(1-heteroaryl)are as defined above; where R₂ is as defined in claim 1; and

[1050] PROTECTING GROUP is t-butoxycarbonyl, benzyloxycarbonyl, formyl,trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl,iodoacetyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobomyloxycarbonyl, -phenyl-C(═N)—H, or 1-piperidyloxycarbonyl.

[1051] Additionally disclosed are amine compounds of the formula

[1052] where R₁ is:

[1053] (V) —CH₂-phenyl, where phenyl is substituted with two —F in the3- and 5-positions giving 3,5-difluorophenyl, or

[1054] (VI) —(CH₂)_(n1)-(R_(1-heteroaryl)), where n1 andR_(1-heteroaryl) are as defined above; and

[1055] where R₂ is as defined in claim 1.

[1056] Addtionally disclosed are lactone compounds of the formula

[1057] where R₁ is:

[1058] (I) C₁-C₆ alkyl, unsubstituted or substituted with one, two orthree C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —NH₂, —C≡N, —CF₃, or —N₃,

[1059] (II) —(CH₂)₁₋₂—S—CH₃,

[1060] (III) —CH₂—CH₂—S—CH₃,

[1061] (IV) —CH₂—(C₂-C₆ alkenyl) unsubstituted or substituted by one —F,

[1062] (V) —(CH₂)₀₋₃-(R_(1-aryl)) where R_(1-aryl) is phenyl,1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinylunsubstituted or substituted on the aryl ring with one or two of thefollowing substituents which can be the samne or different:

[1063] (A) C₁-C₃ alyl,

[1064] (B) —CF₃,

[1065] (C) —F, Cl, —Br and —I,

[1066] (D) C₁-C₃ alkoxy,

[1067] (E) —O—CF₃,

[1068] (F) —NH₂,

[1069] (G) —OH, or

[1070] (H)—C≡N,

[1071] (VI) —(CH₂)_(n1)-(R_(1-heteroaryl)) where n₁ is 0, 1,2, or 3 andR_(1-heteroaryl) is:

[1072] (A) pyridinyl,

[1073] (B) pyrimidinyl,

[1074] (C) quinolinyl,

[1075] (D) indenyl,

[1076] (E) indanyl,

[1077] (F) benzothiophenyl,

[1078] (G) indolyl,

[1079] (H) indolinyl,

[1080] (I) pyridazinyl,

[1081] (J) pyrazinyl,

[1082] (K) isoindolyl,

[1083] (L) isoquinolyl,

[1084] (M) quinazolinyl,

[1085] (N) quinoxalinyl,

[1086] (O) phthalazinyl,

[1087] (P) imidazolyl,

[1088] (Q) isoxazolyl,

[1089] (R) pyrazolyl,

[1090] (S) oxazolyl,

[1091] (T) thiazolyl,

[1092] (U) indolizinyl,

[1093] (V) indazolyl,

[1094] (W) benzothiazolyl,

[1095] (X) benzimidazolyl,

[1096] (Y) benzofuranyl,

[1097] (Z) furanyl,

[1098] (AA) thienyl,

[1099] (BB) pyrrolyl,

[1100] (CC) oxadiazolyl,

[1101] (DD) thiadiazolyl,

[1102] (EE) triazolyl,

[1103] (FF) tetrazolyl,

[1104] (GG) 1,4-benzodioxan

[1105] (HH) purinyl,

[1106] (II) oxazolopyridinyl,

[1107] (JJ) imidazopyridinyl,

[1108] (KK) isothiazolyl,

[1109] (LL) naphthyridinyl,

[1110] (MM) cinnolinyl,

[1111] (NN) carbazolyl,

[1112] (OO) β-carbolinyl,

[1113] (PP) isochromanyl,

[1114] (QQ) chromanyl,

[1115] (RR) furazanyl,

[1116] (SS) tetrahydroisoquinoline,

[1117] (TT) isoindolinyl,

[1118] (UU) isobenzotetrahydrofuranyl,

[1119] (VV) isobenzotetrahydrothienyl,

[1120] (WW) isobenzothiophenyl,

[1121] (XX) beiizoxazolyl, or

[1122] (YY) pyridopyridinyl,

[1123] where the R_(1-heteroaryl) group is bonded to —(CH₂)₀₋₃- by anyring atom of the parent R_(N-heteroaryl) group substituted by hydrogensuch that the new bond to the R_(1-heteroaryl) group replaces thehydrogen atom and its bond, where heteroaryl is unsubstituted orsubstituted with one or two:

[1124] (1) C₁-C₃ alkyl,

[1125] (2) CF₃,

[1126] (3) —F, Cl, —Br, or —I,

[1127] (4) C₁-C₃ alkoxy,

[1128] (5) —O—CF₃,

[1129] (6) —NH₂,

[1130] (7) —OH, or

[1131] (8) —C≡N,

[1132] with the proviso that when ni is zero R_(1-heteroaryl) is notbonded to the carbon chain by nitrogen, or

[1133] (VII) (CH₂)_(n1)-(R_(1-heterocycle)) where n₁ is as defined aboveand R_(1-heterocycle) is:

[1134] (A) morpholinyl,

[1135] (B) thiomorpholinyl,

[1136] (C) thiomorpholinyl S-oxide,

[1137] (D) thiomorpholinyl S,S-dioxide,

[1138] (E) piperazinyl,

[1139] (F) homopiperazinyl,

[1140] (G) pyrrolidinyl,

[1141] (H) pyrrolinyl,

[1142] (I) tetrahydropyranyl,

[1143] (J) piperidinyl,

[1144] (K) tetrahydrofuranyl, or

[1145] (L) tetrahydrothiophenyl,

[1146] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heteroaryl) group replaces the hydrogen atom and itsbond, where heterocycle is unsubstituted or substituted with one or two:

[1147] (1) ═O,

[1148] (2) C₁-C₃ alkyl,

[1149] (3) —CF₃,

[1150] (4) —F, Cl, —Br and —I,

[1151] (5) C₁-C₃ alkoxy,

[1152] (6) —O—CF₃,

[1153] (7) —NH₂,

[1154] (8) —OH, or

[1155] (9) —CN,

[1156] with the proviso that when n, is zero R_(1-heterocycle) is notbonded to the carbon chain by nitrogen;

[1157] where R₂ is:

[1158] (I) —H

[1159] (II) C₁-C₆ alkyl, or

[1160] (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is (C₃-C₆)cycloalkyl, R_(1-aryl)or R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as definedabove,

[1161] where R_(N) is:

[1162] (I) R_(N-1)-X_(N)- where X_(N) is:

[1163] (A) —CO—,

[1164] (B) —SO₂—,

[1165] (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and are—H or C₁-C₄ alkyl,

[1166] (D) —CO—(CR′R″)₁₋₆—X_(N-1) where X_(N-1) is —O—, —S—and —NR′R″-and where R′ and R″ are as defined above,

[1167] (E) a single bond; where R_(N-1) is:

[1168] (A) R_(N-aryl) where R_(N-aryl) is phenyl, 1-naphthyl and2-naphthyl unsubstituted or substituted with one, two, three or four ofthe following substituents which can be the same or different and are:

[1169] (1) C₁-C₆ alkyl,

[1170] (2) —F, —Cl, —Br, or —I,

[1171] (3) —OH,

[1172] (4) —NO₂,

[1173] (5) —CO—OH,

[1174] (6) —C=N,

[1175] (7) —CO—NR_(N-2) R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are:

[1176] (a) —H,

[1177] (b) —C₁-C₆ alkyl unsubstituted or substituted with one

[1178] (i) —OH, or

[1179] (ii) —NH2,

[1180] (c) —C₁-C₆ alkyl unsubstituted or substituted with one to three—F, —Cl, —Br, or —I,

[1181] (d) —C₃-C₇ cycloalkyl,

[1182] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[1183] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[1184] (g) —C₁-C₆ alkenyl with one or two double bonds,

[1185] (h) —C₁-C₆ alkynyl with one or two triple bonds,

[1186] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[1187] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[1188] (k) R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above,

[1189] (8) —CO—(C₃-C₁₂ alkyl),

[1190] (9) —CO—(C₃-C₆ cycloalkyl),

[1191] (10) —CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove,

[1192] (11) —CO—R_(1-heterocycle) where R_(1-heterocycle) is as definedabove,

[1193] (12) —CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with one or two C₁-C₃ alkyl,

[1194] (13) —CO—O—R_(N-5) where R_(N-5) is:

[1195] (a) C₁-C₆ alky, or

[1196] (b) (CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[1197] (14) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are as definedabove,

[1198] (15) —SO—(C₁-C₈ alkyl),

[1199] (16) —SO₂—(C₃-C₁₂ alkyl),

[1200] (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,

[1201] (18) —NH—CO—N(C₁-C₃ aikyl)₂,

[1202] (19) —N—CS—N(C₁-C₃ alkyl)₂,

[1203] (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as definedabove,

[1204] (21) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) can be the same ordifferent and are as defined above,

[1205] (22) —R_(N-4) where R_(N-4) is as defined above,

[1206] (23) —O—CO—(C₁-C₆ alkyl),

[1207] (24) —O—CO—N(Cf-C₃ alkyl)₂,

[1208] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[1209] (26) —O—(C₁-C₆ alkyl),

[1210] (27) —O—(C₂-C₅ alkyl)-COOH,

[1211] (28) —S—(C₁-C₆ alkyl),

[1212] (29) C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3, 4, or5 —F,

[1213] (30) —O—(C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3,4, or 5 —F, or

[1214] (31) —O-φ,

[1215] (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is:

[1216] (A) pyridinyl,

[1217] (B) pyrimidinyl,

[1218] (C) quinolinyl,

[1219] (D) indenyl,

[1220] (E) indanyl,

[1221] (F) benzothiophenyl,

[1222] (G) indolyl,

[1223] (H) indolinyl,

[1224] (I) pyridazinyl,

[1225] (J) pyrazinyl,

[1226] (K) isoindolyl,

[1227] (L) isoquinolyl,

[1228] (M) quinazolinyl,

[1229] (N) quinoxalinyl,

[1230] (O) phthalazinyl,

[1231] (P) imidazolyl,

[1232] (Q) isoxazolyl,

[1233] (R) pyrazolyl,

[1234] (S) oxazolyl,

[1235] (T) thiazolyl,

[1236] (U) indolizinyl,

[1237] (V) indazolyl,

[1238] (W) benzothiazolyl,

[1239] (X) benzimidazolyl,

[1240] (Y) benzofiranyl,

[1241] (Z) fuiranyl,

[1242] (AA) thienyl,

[1243] (BB) pyrrolyl,

[1244] (CC) oxadiazolyl,

[1245] (DD) thiadiazolyl,

[1246] (EE) triazolyl,

[1247] (FF) tetrazolyl,

[1248] (GG) 1,4-benzodioxan

[1249] (HH) purinyl,

[1250] (II) oxazolopyridinyl,

[1251] (JJ) imidazopyridinyl,

[1252] (KK) isothiazolyl,

[1253] (LL) naphthyridinyl,

[1254] (MM) cinnolinyl,

[1255] (NN) carbazolyl,

[1256] (OO) β-carbolinyl,

[1257] (PP) isochromanyl,

[1258] (QQ) chromanyl,

[1259] (RR) furazanyl,

[1260] (SS) tetrahydroisoquinoline,

[1261] (TT) isoindolinyl,

[1262] (UU) isobenzotetrahydrofuranyl,

[1263] (VV) isobenzotetrahydrothienyl,

[1264] (WW) isobenzothiophenyl,

[1265] (XX) benzoxazolyl, or

[1266] (YY) pyridopyridinyl,

[1267] where the R_(N-heteroaryl) group is bonded by any atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(N-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is unsubstituted or substituted with one or two:

[1268] (1) C₁-C₆ alkyl,

[1269] (2) —F, —Cl, —Br, or —I,

[1270] (3) —OH,

[1271] (4) —NO₂,

[1272] (5) —CO—OH,

[1273] (6) —CH≡N,

[1274] (7) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are:

[1275] (a) —H,

[1276] (b) —C₁-C₆ alkyl unsubstituted or substituted with one

[1277] (i) —OH, or

[1278] (ii) —NH₂,

[1279] (c) —C₁-C₆ alkyl unsubstituted or substituted with 1, 2, or 3 —F,—Cl, —Br, or —I,

[1280] (d) —C₃-C₇ cycloalkyl,

[1281] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[1282] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[1283] (g) —C₁-C₆ alkenyl with one or two double bonds,

[1284] (h) —C₁-C₆ alkynyl with one or two triple bonds,

[1285] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[1286] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[1287] (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above,

[1288] (8) —CO—(C₃-C₁₂ alkyl),

[1289] (9) —CO—(C₃-C₆ cycloalkyl),

[1290] (10) —CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove,

[1291] (11) —CO—R_(1-heterocycle) where R_(1-heterocycle) is as definedabove,

[1292] (12) —CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with one or two C₁-C₃ alkyl,

[1293] (13) —CO—O—R_(N-5) where R_(N-5) is:

[1294] (a) C₁-C₆ alkyl, or

[1295] (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[1296] (14) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are as definedabove,

[1297] (15) —SO—(C₁-C₈ alkyl),

[1298] (16) —SO₂(C₃-C₁₂ alkyl),

[1299] (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,

[1300] (18) —NH—CO—N(C₁-C₃ alkyl)₂,

[1301] (19) —N—CS—N(C₁-C₃ alkyl)₂,

[1302] (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as definedabove,

[1303] (21) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) can be the same ordifferent and are as defined above,

[1304] (22) —R_(N-4) where R_(N-4) is as defined above,

[1305] (23) —O—CO—(C₁-C₆ alkyl),

[1306] (24) —O—CO—N(C₁-C₃ alkyl)₂,

[1307] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[1308] (26) —O—(C₁-C₆ alkyl),

[1309] (27) —O—(C₂-C₅ alkyl)-COOH, or

[1310] (28) —S—(C₁-C₆ alkyl),

[1311] (C) —R_(N-aryl)-R_(N-aryl) where —R_(N-aryl) is as defined above,

[1312] (D) —R_(N-aryl)-R_(N-heteroaryl) where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[1313] (E) —R_(N-heteroaryl) R_(N-aryl) where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[1314] (F) R_(N-heteroaryl)-R_(N-heteroaryl) where R_(N-heteroaryl) isas defined above,

[1315] (G) —R_(N-aryl)-O—R_(N-aryl) where —R_(Naryl) is as definedabove,

[1316] (H) —R_(N-aryl)—S—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[1317] (I) —R_(N-hteroaryl)-O—R_(N-heteroaryl) where R_(N-heteroaryl) isas defined above,

[1318] (J) —R_(N-heteroaryl)—S—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[1319] (K) —R_(N-aryl)CO—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[1320] (L) —R_(N-aryl)—CO—R_(N-heteroaryl) where —R_(Naryl) andR_(N-heteroaryl) are as defined above,

[1321] (M) —R_(N-aryl)—SO₂—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[1322] (N) —R_(N-heteroaryl)—CO—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[1323] (O) —R_(N-heteroaryl)-SO₂—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[1324] (P) —R_(N-aryl)-O—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[1325] (Q) —R_(N-aryl)—S—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[1326] (R) —R_(N-heteroaryl—O—(C) ₁-C₈ alkyl)-φ where R_(N-heteroaryl)is as defined above, or

[1327] (S) —R_(N-heteroaryl)—S—(C₁-C₈ alkyl)-φ where R_(N-heteroaryl) isas defined above,

[1328] (II) A—X_(N)- where X_(N) is —CO—, wherein A is

[1329] (A) —T-E—(Q)m′,

[1330] (1) where —T is

[1331] where

[1332] (a) x=1 when y=1 and x=2 when y=0,

[1333] (b) m is 0, 1, 2 or 3,

[1334] (c) the values of x and y vary independently on each carbon whenm is 2 and 3, and

[1335] (d) R′″ varies independently on each carbon and is H, (C1-C2)alkyl, phenyl, or phenyl(C1-C3)alkyl;

[1336] (2) -E is

[1337] (a) C₁-C₅ alkyl, but only if m′ does not equal 0,

[1338] (b) methylthioxy(C₂-C₄)alkyl,

[1339] (c) an aryl group having 5 to 7 atoms when monocyclic or having 8to 12 atoms when fused,

[1340] (d) a heterocyclic group having 5 to 7 atoms when monocyclic orhaving 8 to 12 atoms when fused,

[1341] (e) a mono or fused ring cycloalkyl group having 5 to 10 carbonatoms,

[1342] (f) biphenyl,

[1343] (g) diphenyl ether,

[1344] (h) diphenylketone,

[1345] (i) phenyl(C₁-C₈)alkyloxyphenyl, or

[1346] (j) C₁-C₆ alkoxy;

[1347] (3) —Q is

[1348] (a) C₁-C₃ alkyl,

[1349] (b) C₁-C₃ alkoxy,

[1350] (c) C₁-C₃ alkylthioxy,

[1351] (d) C₁-C₆ alkylacylamino,

[1352] (e) C₁-C₆ alkylacyloxy,

[1353] (f) amido (including primary, C₁-C₆ alkyl and phenyl secondaryand tertiary amino moieties),

[1354] (g) C₁-C₆ alkylamino

[1355] (h) phenylamino,

[1356] (i) carbamyl (including C₁-C₆ alkyl and phenyl amides andesters),

[1357] (j) carboxyl (including C₁-C₆ alkyl and phenyl esters),

[1358] (k) carboxy(C₂-C₅)alkoxy,

[1359] (l carboxy(C₂-C₅)alkylthioxy,

[1360] (m) heterocyclylacyl,

[1361] (n) heteroarylacyl, or

[1362] (o) hydroxyl;

[1363] (4)m′ is 0, 1, 2 or 3;

[1364] (B) -E(Q)_(m″) wherein E and —Q are as defined as above and m″ is0, 1, 2, or 3;

[1365] (C) —T-E wherein -E and —Q are as defined as above; or

[1366] (D) -E wherein -E is as defined as above;

[1367] (III) —CO—(C₁-C₆ alkyl) where alkyl is unsubstituted orsubstituted with one or two:

[1368] (A) —OH,

[1369] (B) —C₁-C₆ alkoxy,

[1370] (C) —C₁-C₆ thioalkoxy,

[1371] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[1372] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1373] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[1374] (G) —SO₂—(C₁-C₈ alkyl),

[1375] (H) —SO₂—NR_(N-2) R_(N-3) where R_(N-2) and R_(N-3) are the sameor different and are as defined above,

[1376] (I) —NH—CO—(C₁-C₆ alkyl),

[1377] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[1378] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1379] (L) —R_(N-4) where R_(N-4) is as defined above,

[1380] (M) —O—CO—(C₁-C₆ alkyl),

[1381] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) is the same ordifferent and are as defined above, or

[1382] (O) —O—(C₁-C₅ alkyl)-COOH,

[1383] (IV) —CO—(C₁-C₃ alkyl)-O—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with one or two

[1384] (A) —OH,

[1385] (B) —C₁-C₆ alkoxy,

[1386] (C) —C₁-C₆ thioalkoxy,

[1387] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[1388] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1389] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[1390] (G) —SO₂—(C₁-C₈ alkyl),

[1391] (H) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1392] (I) —NH—CO—(C₁-C₆ alkyl),

[1393] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[1394] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1395] (L) —R_(N-4) where R_(N-4) is as defined above,

[1396] (M) —O—CO—(C₁-C₆ alkyl),

[1397] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) are the same ordifferent and are as defined above, or

[1398] (O) —O—(C₁-C₅ alkyl)-COOH,

[1399] (V) —CO—(C₁-C₃ alkyl)-S—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with one or two

[1400] (A) —OH,

[1401] (B) —C₁-C₆ alkoxy,

[1402] (C) —C₁-C₆ thioalkoxy,

[1403] (D) —CO—0—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[1404] (E) —CO—NR_(N-2) R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1405] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[1406] (G) —SO₂—(C₁-C₈ alkyl),

[1407] (H) —SO2—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1408] (I) —NH—CO—(C₁-C₆ alkyl),

[1409] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[1410] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1411] (L) —R_(N-4) where R_(N-4) is as defined above,

[1412] (M) —O—CO—(C₁-C₆ alkyl),

[1413] (N) —O—CO—NRN8R_(N-8) where the R_(N-8) are the same or differentand are as defined above, or

[1414] (O) —O—(C₁-C₅ alkyl)-COOH,

[1415](VI)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl))where R_(N-aryl) and R_(N-heteroaryl) are as defined above, whereR_(N-10) is:

[1416] (A) —H,

[1417] (B) C₁-C₆ alkyl,

[1418] (C) C₃-C₇ cycloalkyl,

[1419] (D) C₂-C₆ alkenyl with one double bond,

[1420] (E) C₂-C₆ alkynyl with one triple bond,

[1421] (F) R_(1-aryl) where R_(1-aryl) is as defined above, or

[1422] (G) R_(N-heteroaryl) where R_(N-heteroayl) is as defined above.

[1423] Disclosed is a method of treating a patient who has, or inpreventing a patient from getting, a disease or condition selected fromAlzheimer's disease, mild cognitive impairment, Down's syndrome,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type,cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy bodytype of Alzheimer's disease or central or peripheral amyloid diseasesand who is in need of such treatment which comprises administration of atherapeutically effective amount of a hydroxyethylene compound offormula (XII)

[1424] where R₁ is:

[1425] (I) C₁-C₆ alkyl, unsubstituted or substituted with one, two orthree C₁-C₃ alkyl, —F, —Cl, —Br, —1, —OH, —NH₂, —C≡N, —CF₃, or —N₃,

[1426] (II) —(CH₂)₁ ₂—S—CH₃,

[1427] (III) —CH₂—CH₂—S—CH₃,

[1428] (IV) —CH₂—(C₂-C₆ alkenyl) unsubstituted or substituted by one —F,

[1429] (V) —(CH₂)0-3-(R_(1-aryl)) where R_(1-aryl) is phenyl,1-naphthyl, 2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinylunsubstituted or substituted on the aryl ring with one or two of thefollowing substituents which can be the same or different:

[1430] (A) C₁-C₃ alkyl,

[1431] (B) —CF₃,

[1432] (C) —F, Cl, —Br and —I,

[1433] (D) C₁-C₃ alkoxy,

[1434] (E) —O—CF₃,

[1435] (F) —NH₂,

[1436] (G) —OH, or

[1437] (H) —C—N,

[1438] (VI) —(CH₂)_(n1)-(R_(1-heteroaryl)) where n₁ is 0, 1, 2, or 3 andR_(1-heteroaryl) is:

[1439] (A) pyridinyl,

[1440] (B) pyrimidinyl,

[1441] (C) quinolinyl,

[1442] (D) indenyl,

[1443] (E) indanyl,

[1444] (F) benzothiophenyl,

[1445] (G) indolyl,

[1446] (H) indolinyl,

[1447] (I) pyridazinyl,

[1448] (J) pyrazinyl,

[1449] (K) isoindolyl,

[1450] (L) isoquinolyl,

[1451] (M) quinazolinyl,

[1452] (N) quinoxalinyl,

[1453] (O) phthalazinyl,

[1454] (P) imidazolyl,

[1455] (Q) isoxazolyl,

[1456] (R) pyrazolyl,

[1457] (S) oxazolyl,

[1458] (T) thiazolyl,

[1459] (U) indolizinyl,

[1460] (V) indazolyl,

[1461] (W) benzothiazolyl,

[1462] (X) benzimidazolyl,

[1463] (Y) benzofiranyl,

[1464] (Z) furanyl,

[1465] (AA) thienyl,

[1466] (BB) pyrrolyl,

[1467] (CC) oxadiazolyl,

[1468] (DD) thiadiazolyl,

[1469] (EE) triazolyl,

[1470] (FF) tetrazolyl,

[1471] (GG) 1,4-benzodioxan

[1472] (HH) purinyl,

[1473] (II) oxazolopyridinyl,

[1474] (JJ) imidazopyridinyl,

[1475] (KK) isothiazolyl,

[1476] (LL) naphthyridinyl,

[1477] (MM) cinnolinyl,

[1478] (NN) carbazolyl,

[1479] (OO) β-carbolinyl,

[1480] (PP) isochromanyl,

[1481] (QQ) chromanyl,

[1482] (RR) furazanyl,

[1483] (SS) tetrahydroisoquinoline,

[1484] (TT) isoindolinyl,

[1485] (UU) isobenzotetrahydrofuranyl,

[1486] (VV) isobenzotetrahydrothienyl,

[1487] (WW) isobenzothiophenyl,

[1488] (XX) benzoxazolyl, or

[1489] (YY) pyridopyridinyl,

[1490] where the R_(1-heteroaryl) group is bonded to —(CH₂)₀₋₃- by anyring atom of the parent R_(N-heteroaryl) group substituted by hydrogensuch that the new bond to the R_(1-heteroaryl) group replaces thehydrogen atom and its bond, where heteroaryl is unsubstituted orsubstituted with one or two:

[1491] (1) C₁-C₃ alkyl,

[1492] (2)—CF₃,

[1493] (3) —F, Cl, —Br, or —I,

[1494] (4) C₁-C₃ alkoxy,

[1495] (5) —O—CF₃,

[1496] (6) —NH₂,

[1497] (7) —OH, or

[1498] (8) —C≡N,

[1499] with the proviso that when n₁ is zero R_(1-heteroaryl) is notbonded to the carbon chain by nitrogen, or

[1500] (VII) —(CH₂)_(n1)-(R_(1-heterocycle)) where n₁ is as definedabove and R_(1-heterocycle) is:

[1501] (A) morpholinyl,

[1502] (B) thiomorpholinyl,

[1503] (C) thiomorpholinyl S-oxide,

[1504] (D) thiomorpholinyl S,S-dioxide,

[1505] (E) piperazinyl,

[1506] (F) homopiperazinyl,

[1507] (G) pyrrolidinyl,

[1508] (H) pyrrolinyl,

[1509] (I) tetrahydropyranyl,

[1510] (J) piperidinyl,

[1511] (K) tetrahydrofuranyl, or

[1512] (L) tetrahydrothiophenyl,

[1513] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heteroaryl) group replaces the hydrogen atom and itsbond, where heterocycle is unsubstituted or substituted with one or two:

[1514] (1) ═O,

[1515] (2) C₁-C₃ alkyl,

[1516] (3) CF₃,

[1517] (4) —F, Cl, —Br and —I,

[1518] (5) C₁-C₃ alkoxy,

[1519] (6) —O—CF₃,

[1520] (7) —NH₂,

[1521] (8) —OH, or

[1522] (9) —C≡N,

[1523] with the proviso that when n₁ is zero R_(1-heterocycle) is notbonded to the carbon chain by nitrogen;

[1524] where R₂ is:

[1525] (I) —H.

[1526] (II) C₁-C₆ alky, or

[1527] (III) —(CH₂)₀₋₄—R₂ ₁ where R₂ ₁ is (C₃-C₆)cycloalkyl, R_(1-aryl)or R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as definedabove,

[1528] where R_(N) is:

[1529] (I) R_(N-1)-X_(N)- where X_(N) is:

[1530] (A) —CO—,

[1531] (B) —SO₂—,

[1532] (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and are—H or C₁-C₄ alkyl,

[1533] (D) —CO—(CR′R″)₁₋₆-X_(N-1) where X_(N-1) is —O—, —S—and —NR′R″-and where R′ and R″ are as defined above,

[1534] (E) a single bond;

[1535] where R_(N-1) is:

[1536] (A) R_(N-aryl) where R_(Naryl) is phenyl, 1-naphthyl and2-naphthyl unsubstituted or substituted with one, two, three or four ofthe following substituents which can be the same or different and are:

[1537] (1) C₁-C₆ alkyl

[1538] (2)—F, —Cl, —Br, or —I,

[1539] (3) —OH,

[1540] (4) —NO₂,

[1541] (5) —CO—OH,

[1542] (6) —C≡N,

[1543] (7) —CO—NR_(N-2) R_(N-3) where R_(N-2) and R_(N-3) are the sameor different and are:

[1544] (a) —H,

[1545] (b) —C₁-C₆ alkyl unsubstituted or substituted with one

[1546] (i) —OH, or

[1547] (ii) —NH₂,

[1548] (c) —C₁-C₆ alkyl unsubstituted or substituted with one to three—F, —Cl, —Br, or —I,

[1549] (d) —C₃-C₇ cycloalkyl,

[1550] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[1551] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[1552] (g) —C₁-C₆ alkenyl with one or two double bonds,

[1553] (h) —C₁-C₆ alkynyl with one or two triple bonds,

[1554] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[1555] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[1556] (k) R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above,

[1557] (8) —CO—(C₃-C₁₂ alkyl),

[1558] (9) —CO—(C₃-C₆ cycloalkyl),

[1559] (10) —CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove,

[1560] (11) —CO—R_(1-heterocycle) where R_(1-heterocycle) is as definedabove,

[1561] (12) —CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with one or two C₁-C₃ alkyl,

[1562] (13) —CO—O—R_(N-5) where R_(N-5) is:

[1563] (a) C₁-C₆ alkyl, or

[1564] (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[1565] (14) —SO₂-NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are as definedabove,

[1566] (15) —SO—(C₁-C₈ alkyl),

[1567] (16) —SO₂(C₃-C₁₂ alkyl),

[1568] (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,

[1569] (18) —NH—CO—N(C₁-C₃ alkyl)₂,

[1570] (19) —N—CS—N(C₁-C₃ alkyl)₂,

[1571] (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as definedabove,

[1572] (21) —NR_(N-2) R_(N-3) where R_(N-2) and R_(N-3) can be the sameor different and are as defined above,

[1573] (22) —R_(N-4) where R_(N-4) is as defined above,

[1574] (23) —O—CO—(C₁-C₆ alkyl),

[1575] (24) —O—CO—N(C₁-C₃ alkyl)₂,

[1576] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[1577] (26) —O—(C₁-C₆ alkyl),

[1578] (27) —O—(C₂-C₅ alkyl)-COOH,

[1579] (28) —S—(C₁-C₆ alkyl),

[1580] (29) C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3, 4, or5 —F,

[1581] (30) —O—(C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3,4, or 5—F, or

[1582] (31) —O—,

[1583] (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is:

[1584] (A) pyridinyl,

[1585] (B) pyrimidinyl,

[1586] (C) quinolinyl,

[1587] (D) indenyl,

[1588] (E) indanyl,

[1589] (F) benzothiophenyl,

[1590] (G) indolyl,

[1591] (H) indolinyl,

[1592] (I) pyridazinyl,

[1593] (J) pyrazinyl,

[1594] (K) isoindolyl,

[1595] (L) isoquinolyl,

[1596] (M) quinazolinyl,

[1597] (N) quinoxalinyl,

[1598] (O) phthalazinyl,

[1599] (P) imidazolyl,

[1600] (Q) isoxazolyl,

[1601] (R) pyrazolyl,

[1602] (S) oxazolyl,

[1603] (T) thiazolyl,

[1604] (U) indolizinyl,

[1605] (V) indazolyl,

[1606] (W) benzothiazolyl,

[1607] (X) benzimidazolyl,

[1608] (Y) benzofuranyl,

[1609] (Z) furanyl,

[1610] (AA) thienyl,

[1611] (BB) pyrrolyl,

[1612] (CC) oxadiazolyl,

[1613] (DD) thiadiazolyl,

[1614] (EE) triazolyl,

[1615] (FF) tetrazolyl,

[1616] (GG) 1,4-benzodioxan

[1617] (HH) purinyl,

[1618] (II) oxazolopyridinyl,

[1619] (JJ) imidazopyridinyl,

[1620] (KK) isothiazolyl,

[1621] (LL) naphthyridinyl,

[1622] (MM) cinnolinyl,

[1623] (NN) carbazolyl,

[1624] (OO) β-carbolinyl,

[1625] (PP) isochromanyl,

[1626] (QQ) chromanyl,

[1627] (RR) furazanyl,

[1628] (SS) tetrahydroisoquinoline,

[1629] (TT) isoindolinyl,

[1630] (UU) isobenzotetrahydrofuranyl,

[1631] (VV) isobenzotetrahydrothienyl,

[1632] (WW) isobenzothiophenyl,

[1633] (XX) benzoxazolyl, or

[1634] (YY) pyridopyridinyl,

[1635] where the R_(N-heteroayl) group is bonded by any atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(N-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is unsubstituted or substituted with one or two:

[1636] (1) C₁-C₆ alkyl,

[1637] (2) —F, —Cl, —Br, or —I,

[1638] (3) —OH,

[1639] (4) —NO₂,

[1640] (5) —CO—OH,

[1641] (6) —C≡N,

[1642] (7) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are:

[1643] (a) —H,

[1644] (b) —C₁-C₆ alkyl unsubstituted or substituted with one

[1645] (i) —OH, or

[1646] (ii) —NH₂,

[1647] (c) —C₁-C₆ alkyl unsubstituted or substituted with 1, 2, or 3 —F,—Cl, —Br, or —I,

[1648] (d) —C₃-C₇ cycloalkyl,

[1649] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[1650] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[1651] (g) —C₁-C₆ alkenyl with one or two double bonds,

[1652] (h) —C₁-C₆ alkynyl with one or two triple bonds,

[1653] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[1654] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[1655] (k) —R_(1-heteroayl) where R_(1-heteroaryl) is as defined above,

[1656] (8) —CO—(C₃-C₁₂ alkyl),

[1657] (9) —CO—(C₃-C₆ cycloalkyl),

[1658] (10) —CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove,

[1659] (11) —CO—R_(1-heterocycle) where R_(1-heterocycle) is as definedabove,

[1660] (12) —CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with one or two C₁-C₃ alkyl,

[1661] (13) —CO—O—R_(N-5) where R_(N-5) is:

[1662] (a) C₁-C₆ alkyl, or

[1663] (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[1664] (14) —SO₂—NR_(N-2) R_(N-3)where R_(N-2) and R_(N-3) are asdefined above,

[1665] (15) —SO—(C₁-C₈ alkyl),

[1666] (16) —SO₂(C₃-C₁₂ alkyl),

[1667] (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,

[1668] (18) —NH—CO—N(C₁-C₃ alkyl)₂,

[1669] (19) —N—CS—N(C₁-C₃ alkyl)₂,

[1670] (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as definedabove,

[1671] (21) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) can be the same ordifferent and are as defined above,

[1672] (22) —R_(N-4) where R_(N-4) is as defined above,

[1673] (23) —O—CO—(C₁-C₆ alkyl),

[1674] (24) —O—CO—N(C₁-C₃ alkyl)₂,

[1675] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[1676] (26) —O—(C₁-C₆ alkyl),

[1677] (27) —O—(C₂-C₅ alkyl)-COOH, or

[1678] (28) —S—(C₁-C₆ alkyl),

[1679] (C) —R_(N-aryl)R_(N-aryl) where —R_(N-aryl) is as defined above,

[1680] (D) —R_(N-aryl)-R_(N-heteroaryl) where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[1681] (E) —R_(N-heteroaryl)-R_(N-aryl) where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[1682] (F) —R_(N-heteroaryl)-R_(N-heteroaryl) where R_(N-heteroaryl) isas defined above,

[1683] (G) —R_(N-aryl)-O—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[1684] (H) —R_(N-aryl)—S—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[1685] (I) —R_(N-heteroaryl)-O—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[1686] (J) —R_(N-heteroaryl)—S—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[1687] (K) —R_(N-aryl)—CO—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[1688] (L) —R_(N-aryl)—CO—R_(N-heteroaryl) where —R_(N-aryl) andR_(N-heteroaryl) are as defined above,

[1689] (M) —R_(N-aryl)—SO₂—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[1690] (N) —R_(N-heteroaryl)—CO—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[1691] (O) —R_(N-heteroayl)—SO₂—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[1692] (P) —R_(N-aryl)-O—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[1693] (Q) —R_(N-aryl)—S—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[1694] (R) —R_(N-heteroaryl)-O—(C₁-C₈ alkyl)-φ where R_(N-heteroaryl) isas defined above, or

[1695] (S) —R_(N-heteroaryl)—S—(C₁-C₈ alkyl)-φ where RN-heteroaryl is asdefined above,

[1696] (II) A—X_(N)- where X_(N) is —CO—, wherein A is

[1697] (A) —T-E(Q)_(m′),

[1698] (1) where —T is

[1699] where

[1700] (a) x=1 when y=1 and x=2 when y=0,

[1701] (b) m is 0, 1, 2 or 3,

[1702] (c) the values of x and y vary independently on each carbon whenm is 2 and 3, and

[1703] (d) R′″ varies independently on each carbon and is H, (C₁-C₂)alkyl, phenyl, or phenyl(C₁-C₃)alkyl;

[1704] (2) -E is

[1705] (a) C₁-C₅ alkyl, but only if m′ does not equal 0,

[1706] (b) methylthioxy(C₂-C₄)alkyl,

[1707] (c) an aryl group having 5 to 7 atoms when monocyclic or having 8to 12 atoms when fused,

[1708] (d) a heterocyclic group having 5 to 7 atoms when monocyclic orhaving 8 to 12 atoms when fused,

[1709] (e) a mono or fused ring cycloalkyl group having 5 to 10 carbonatoms,

[1710] (f) biphenyl,

[1711] (g) diphenyl ether,

[1712] (h) diphenylketone,

[1713] (i) phenyl(C₁-C₈)alkyloxyphenyl, or

[1714] (j) C₁-C₆ alkoxy;

[1715] (3) —Q is

[1716] (a) C₁-C₃ alkyl,

[1717] (b) C₁-C₃ alkoxy,

[1718] (c) C₁-C₃ alkylthioxy,

[1719] (d) C₁-C₆ alkylacylamino,

[1720] (e) C₁-C₆ alkylacyloxy,

[1721] (f) amido (including primary, C₁-C₆ alkyl and phenyl secondaryand tertiary amino moieties),

[1722] (g) C₁-C₆ alkylamino

[1723] (h) phenylamino,

[1724] (i) carbamyl (including C₁-C₆ alkyl and phenyl amides andesters),

[1725] (j) carboxyl (including C₁-C₆ alkyl and phenyl esters),

[1726] (k) carboxy(C₂-C₅)alkoxy,

[1727] (l) carboxy(C₂-C₅)alkylthioxy,

[1728] (m) heterocyclylacyl,

[1729] (n) heteroarylacyl, or

[1730] (o) hydroxyl;

[1731] (4)m′ is 0, 1, 2 or 3;

[1732] (B) -E(Q)_(m″), wherein E and —Q are as defined as above and m″is 0, 1, 2, or 3;

[1733] (C) —T-E wherein -E and —Q are as defined as above; or

[1734] (D) -E wherein -E is as defined as above;

[1735] (III) —CO—(C₁-C₆ alkyl) where alkyl is unsubstituted orsubstituted with one or two:

[1736] (A)—OH,

[1737] (B) —C₁-C₆ alkoxy,

[1738] (C) —C₁-C₆ thioalkoxy,

[1739] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[1740] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1741] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[1742] (G) —SO₂-(C₁-C₈ alkyl),

[1743] (H) —SO2—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1744] (I) —NH—CO—(C₁-C₆ alkyl),

[1745] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[1746] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1747] (L) —R_(N-4) where R_(N-4) is as defined above,

[1748] (M) —O—CO—(C₁-C₆ alkyl),

[1749] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) is the same ordifferent and are as defined above, or

[1750] (O) —O—(C₁-C₅ alkyl)-COOH,

[1751] (IV) —CO—(C₁-C₃ alkyl)-O—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with one or two

[1752] (A) —OH,

[1753] (B) —C₁-C₆ alkoxy,

[1754] (C) —C₁-C₆ thioalkoxy,

[1755] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[1756] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1757] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[1758] (G) —SO₂-(C₁-C₈ alkyl),

[1759] (H) —SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the sameor different and are as defined above,

[1760] (I) —NH—CO—(C₁-C₆ alkyl),

[1761] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[1762] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1763] (L) —R_(N-4) where R_(N-4) is as defined above,

[1764] (M) —O—CO—(C₁-C₆ alkyl),

[1765] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) are the same ordifferent and are as defined above, or

[1766] (O) —O—(C₁-C₅ alkyl)-COOH,

[1767] (V) —CO—(C₁-C3 alkyl)-S—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with one or two

[1768] (A) —OH,

[1769] (B) —C₁-C₆ alkoxy,

[1770] (C) —C₁-C₆ thioalkoxy,

[1771] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[1772] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1773] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[1774] (G) —SO₂—(C₁-C₈ alkyl),

[1775] (H) —SO₂—NR_(N-2) R_(N-3)where R_(N-2) and R_(N-3) are the sameor different and are as defined above,

[1776] (I) —NH—CO—(C₁-C₆ alkyl),

[1777] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[1778] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[1779] (L) —R_(N-4) where R_(N-4) is as defined above,

[1780] (M) —O—CO—(C₁-C₆ alkyl),

[1781] (N) —O—CO—NRN8R_(N-8) where the R_(N-8) are the same or differentand are as defined above, or

[1782] (O) —O—(C₁-C₅ alkyl)-COOH,

[1783] (VI)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))-(CH₂)02—R_(N-aryl)/R_(N-heteroaryl) ) whereR_(N-aryl) and R_(N-heteroaryl) are as defined above, where R_(N-10) is:

[1784] (A) —H,

[1785] (B) C₁-C₆ alkyl,

[1786] (C) C₃-C₇ cycloalkyl,

[1787] (D) C₂-C₆ alkenyl with one double bond,

[1788] (E) C₂-C₆ alkynyl with one triple bond,

[1789] (F) R_(1-aryl) where R_(1-aryl) is as defined above, or

[1790] (G) R_(N-heteroaryl) where R_(N-heteroaryl) is as defined above;

[1791] where B is —O—, —NH—, or —N(C₁-C₆ alkyl)-;

[1792] where R_(C) is:

[1793] (I) —(C₁-C₁₀)alkyl-K₁₋₃ in which:

[1794] (A) the alkyl chain is unsubstituted or substituted with one —OH,

[1795] (B) the alkyl chain is unsubstituted or substituted with oneC₁-C₆ alkoxy unsubstituted or substituted with 1-5 —F,

[1796] (C) the alkyl chain is unsubstituted or substituted with one—O-φ,

[1797] (D) the alkyl chain is unsubstituted or substituted with 1-5 —F,

[1798] (E) the alkyl chain is unsubstituted or substituted with acombination of up to three atoms of oxygen and sulfur each such atomreplacing one carbon,

[1799] (F) each K is:

[1800] (1) H,

[1801] (2) C₁-C₃ alkyl,

[1802] (3) C₁-C₃ alkoxy,

[1803] (4) C₁-C₃ alkylthioxy,

[1804] (5) C₁-C₆ alkylacylamino,

[1805] (6) C₁-C₆ alkylacyloxy,

[1806] (7) amido

[1807] (8) C₁-C₆ alkylamino

[1808] (9) phenylamino,

[1809] (10) carbamyl

[1810] (11) carboxyl

[1811] (12) carboxy(C₂-C₅)alkoxy,

[1812] (13) carboxy(C₂-C₅)alkylthioxy,

[1813] (14) heterocyclylacyl,

[1814] (15) heteroarylacyl,

[1815] (16) amino unsubstituted or substituted with C₁-C₆ alkyl,

[1816] (17) hydroxyl, or

[1817] (18) carboxyl methyl ester;

[1818] (II)—(CH₂)₀₋₃-J-[(-(CH₂)₀₋₃-K]₁₋₃ where K is as defined above andJ is:

[1819] (A) a 5 to 7 atom monocyclic aryl group,

[1820] (B) a 8 to 12 atom multicyclic aryl group,

[1821] (C) a 5 to 7 atom heterocyclic group,

[1822] (D) a 8 to 12 atom multicyclic heterocyclic group, or

[1823] (E) a 5 to 10 atom monocyclic or multicyclic cycloalkyl group;

[1824] (III) —(CH₂)₀₋₃—(C₃-C₇) cycloalkyl where cycloalkyl can beunsubstituted or substituted with one, two or three

[1825] (A) C₁-C₃ alkyl unsubstituted or substituted with 1, 2, 3, or 4—F, —Cl, —Br, or —I,

[1826] (B) —CO—OH,

[1827] (C) —CO—O—(C₁-C₄ alkyl),

[1828] (D) —OH, or

[1829] (E) C₁-C₆ alkoxy,

[1830] (IV) —(CH₂)₂ ₆—OH,

[1831] (V) (CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl) where R_(C−x) and R_(C−y) are-H, C₁-C₄ alkyl and 4 and R_(C-aryl) is the same as R_(N-aryl),

[1832] (VI) —(CH₂)₀₋₄—R_(C-heteroaryl) where R_(C-heteroaryl) is:

[1833] (A) pyridinyl,

[1834] (B) pyrimidinyl,

[1835] (C) quinolinyl,

[1836] (D) indenyl,

[1837] (E) indanyl,

[1838] (F) benzothiophenyl,

[1839] (G) indolyl,

[1840] (H) indolinyl,

[1841] (I) pyridazinyl,

[1842] (J) pyrazinyl,

[1843] (K) isoindolyl,

[1844] (L) isoquinolyl,

[1845] (M) quinazolinyl,

[1846] (N) quinoxalinyl,

[1847] (O) phthalazinyl,

[1848] (P) isoxazolyl,

[1849] (Q) pyrazolyl,

[1850] (R) indolizinyl,

[1851] (S) indazolyl,

[1852] (T) benzothiazolyl,

[1853] (U) benzimidazolyl,

[1854] (V) benzofuranyl,

[1855] (W) furanyl,

[1856] (X) thienyl,

[1857] (Y) pyrrolyl,

[1858] (Z) oxadiazolyl,

[1859] (AA) thiadiazolyl,

[1860] (BB) triazolyl,

[1861] (CC) tetrazolyl,

[1862] (DD) 1,4-benzodioxan

[1863] (EE) purinyl,

[1864] (FF) oxazolopyridinyl,

[1865] (GG) imidazopyridinyl,

[1866] (HH) isothiazolyl,

[1867] (II) naphthyridinyl,

[1868] (JJ) cinnolinyl,

[1869] (KK) carbazolyl,

[1870] (LL) β-carbolinyl,

[1871] (MM) isochromanyl,

[1872] (NN) chromanyl,

[1873] (OO) furazanyl,

[1874] (PP) tetrahydroisoquinoline,

[1875] (QQ) isoindolinyl,

[1876] (RR) isobenzotetrahydrofuranyl,

[1877] (SS) isobenzotetrahydrothienyl,

[1878] (TT) isobenzothiophenyl,

[1879] (UU) benzoxazolyl, or

[1880] (VV) pyridopyridinyl,

[1881] (VII ) —(CH₂)₀₋₄—R_(C-heterocycle) where R_(C-heterocycle) is thesame as R_(1-heterocycle)

[1882] (VIII) —C(R_(C−1))(R_(C−2))—CO—NH—R_(C−3) where R_(C−1) andR_(C−2) are the same or different and are:

[1883] (A) —H,

[1884] (B) —C₁-C₆ alkyl,

[1885] (C) —(C₁-C₄ alkyl)-R_(C′-aryl) where R_(C′-aryl) is as definedabove for R_(1-aryl),

[1886] (D) —(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is asdefined above,

[1887] (E) —(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle) isas defined above,

[1888] (F) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above,

[1889] (G) —R_(C-heterocycle) where R_(C-heterocycle) is as definedabove,

[1890] (H) —(CH₂)₁₄—OH,

[1891] (I) —( CH₂)₁₋₄—R_(C−4)-(CH₂)₁₋₄—R_(C′-aryl) where R_(C−4) is —O—,—S—, —NH—or —NHR_(C−5)- where R_(C−5) is C₁-C₆ alkyl, and whereR_(C′-aryl) is as defined above,

[1892] (J) —(CH₂)₁₋₄—R_(C-4)—(CH₂)₁₋₄—R_(C-heteroaryl) where R_(C-4) andR_(C-heteroaryl) are as defined above, or

[1893] (K) —R_(C′-aryl) where R_(C′-aryl) is as defined above,

[1894] and where R_(C-3) is:

[1895] (A) —H,

[1896] (B) -C₁-C₆ alkyl,

[1897] (C) —R_(C′-aryl) where R_(C′-aryl) is as defined above,

[1898] (D) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above,

[1899] (E) —R_(C-heterocycle) where R_(C-heterocycle) is as definedabove,

[1900] (F) —(C₁-C₄ alkyl)-R_(C′-aryl) where R_(C′-aryl) is as definedabove,

[1901] (G) —(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is asdefined above, or

[1902] (H) —(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle) isas defined above,

[1903] (IX) —CH(φ)₂,

[1904] (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl orheteroaryl ring where heteroaryl is as defined above and phenyl andheteroaryl are unsubstituted or substituted with one, two or three:

[1905] (A) C₁-C₃ alkyl,

[1906] (B) —CF₃,

[1907] (C) —F, Cl, —Br and —I,

[1908] (D) C₁-C₃ alkoxy,

[1909] (E) —OCF₃,

[1910] (F) —NH₂,

[1911] (G) —OH, or

[1912] (H) —C≡N,

[1913] (XI) —CH₂—C≡CH;

[1914] (XII) —(CH₂)₀₋₄ —CHR_(C−5)—(CH₂)₀₋₁-φ where R_(C−5) is:

[1915] (A) H, or

[1916] (B)—CH₂—OH;

[1917] (XIII) —CH(-φ)—CO—O(C₁-C₃ alkyl);

[1918] (XIV) —CH(—CH₂—OH)—CH(—OH)-φ—NO₂;

[1919] (XV) —(CH₂)₂—O—(CH₂)₂—OH;

[1920] (XVI) —CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂;

[1921] (XVII) —(C₂-C₈) alkynyl; or

[1922] (XVIII) —H; or a pharmaceutically acceptable salt thereof.

[1923] Disclosed is the use of a hydroxyethylene compound of formula(XII)

[1924] where R₁, R₂, R_(C), and R_(N) are as defined immediately above,and pharmaceutically acceptable salts thereof for the manufacture of amedicament for use in treating a patient who has, or in preventing apatient from getting, a disease or condition selected from Alzheimer'sdisease, mild cognitive impairment, Down's syndrome, Hereditary CerebralHemorrhage with Amyloidosis of the Dutch-Type, cerebral amyloidangiopathy, degenerative dementia, diffuse Lewy body type of Alzheimer'sdisease or central or preipheral amyloid diseases and who is in need ofsuch treatment.

DETAILED DESCRIPTION OF THE INVENTION

[1925] The present invention provides hydroxyethylene compounds offormula (XII) which are useful in treating and preventing Alzheimer'sdisease. The anti-Alzheimer's hydroxyethylene compounds of formula (XII)are made by methods well known to those skilled in the art from startingcompounds known to those skilled in the art. The process chemistry iswell known to those skilled in the art. The most general process toprepare the hydroxyethylene compounds of formula (XII) is set forth inCHART A, as defined within. The chemistry is straight forward and insummary involves the steps of N-protecting an amino acid (I) startingmaterial to produce the corresponding protected amino acid (II),amino-dehydroxylation of the protected amino acid (II) with theappropriate amine in the presence of a coupling agent to produce thecorresponding protected amide (III), reduction of the protected amide tothe corresponding aldehyde (IV), formation of the terminal olefin asdescribed (V), peracid epoxidation of the olefin (V) to produce thecorresponding epoxide (VI), opening of the epoxide (VI) with an amide(VII) to produce the corresponding protected alcohol (VIII), cyclizationof the protected alcohol (VIII) to produce the protected lactone (IX)which then has the nitrogen protecting group removed to produce thecorresponding amine (X), which is then reacted with an amide formingagent of the formula (R_(N-1)-X_(N))₂O or R_(N-1)-X_(N)-X₂ orR_(N-1)-X_(N)—OH, for example, to produce the lactone (XI), opening ofthe lactone (XI) with a C-terminal amine, R_(C)—NH₂ to produce theanti-Alzheimer hydroxyethylene compounds of formula (XII). One skilledin the art will appreciate that these are all well known reactions inorganic chemistry. A chemist skilled in the art, knowing the chemicalstructure of the biologically active hydroxyethylene compounds offormula (XII) would be able to prepare them by known methods from knownstarting materials without any additional information. The explanationbelow therefore is not necessary but is deemed helpful to those skilledin the art who desire to make the compounds of the present invention.

[1926] The backbone of the compounds of the present invention is ahydroxyethylene moiety. It can be readily prepared by methods disclosedin the literature and known to those skilled in the art. For example,Henning, R. “Synthetic Routes to Different Classes of Natural Productsand Analogs Thereof. Synthesis of Hydroxyethylene Isosteric Dipeptides.”In Organic Synthesis Highlights II; VCH: Weinheim, Germany, 1995; pp251-259 discloses processes to prepare hydroxyethylene type compounds.

[1927] CHART A, as defined within, sets forth a general method used inthe present invention to prepare the appropriately substitutedhydroxyethylene compounds of formula (XII). The anti-Alzheimerhydroxyethylene compounds of formula (XII) are prepared by starting withthe corresponding amino acid (I). The amino acids (I) are well known tothose skilled in the art or can be readily prepared from known compoundsby methods well known to those skilled in the art. The hydroxyethylenecompounds of formula (XII) have at least three enantiomeric centerswhich give 8 enantiomers, the S, S, R stereochemistry being preferred.The first of these enantiomeric centers derives from the amino acidstarting material (I). It is preferred to commercially obtain or producethe desired enantiomer (S) rather than produce an enantiomericallyimpure mixture and then have to separate out the desired enantiomer (S).It is preferred to start the process with enantiomerically pure(S)-amino acid (I) of the same configuration as that of thehydroxyethylene product. For the amino acids (I), R₁ is:

[1928] (I) C₁-C₆ alkyl, unsubstituted or substituted with one, two orthree C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —NH₂, —C≡N, —CF₃, or —N₃,

[1929] (II) —(CH₂)₁₋₂—S—CH₃,

[1930] (III) —CH₂—CH₂—S—CH₃,

[1931] (IV) —CH₂—(C₂-C₆ alkenyl) unsubstituted or substituted by one —F,

[1932] (V) —(CH₂)₀₋₃(R_(1-aryl)) where R_(1-aryl) is phenyl, 1-naphthyl,2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstitutedor substituted on the aryl ring with one or two of the followingsubstituents which can be the same or different:

[1933] (A) C₁-C₃ alkyl,

[1934] (B) —CF₃,

[1935] (C) —F, Cl, —Br and —I,

[1936] (D) C₁-C₃ alkoxy,

[1937] (E) —O—CF₃,

[1938] (F) —NH₂,

[1939] (G) —OH, or

[1940] (H) —C≡N,

[1941] (VI) —(CH₂)_(n1)-(R_(1-heteroaryl)) where n₁ is 0, 1, 2, or 3 andR_(1-heteroaryl) is:

[1942] (A) pyridinyl,

[1943] (B) pyrimidinyl,

[1944] (C) quinolinyl,

[1945] (D) indenyl,

[1946] (E) indanyl,

[1947] (F) benzothiophenyl,

[1948] (G) indolyl,

[1949] (H) indolinyl,

[1950] (I) pyridazinyl,

[1951] (J) pyrazinyl,

[1952] (K) isoindolyl,

[1953] (L) isoquinolyl,

[1954] (M) quinazolinyl,

[1955] (N) quinoxalinyl,

[1956] (O) phthalazinyl,

[1957] (P) imidazolyl,

[1958] (Q) isoxazolyl,

[1959] (R) pyrazolyl,

[1960] (S) oxazolyl,

[1961] (T) thiazolyl,

[1962] (U) indolizinyl,

[1963] (V) indazolyl,

[1964] (W) benzothiazolyl,

[1965] (X) benzimidazolyl,

[1966] (Y) benzofuranyl,

[1967] (Z) furanyl,

[1968] (AA) thienyl,

[1969] (BB) pyrrolyl,

[1970] (CC) oxadiazolyl,

[1971] (DD) thiadiazolyl,

[1972] (EE) triazolyl,

[1973] (FF) tetrazolyl,

[1974] (GG) 1,4-benzodioxan

[1975] (HH) purinyl,

[1976] (II) oxazolopyridinyl,

[1977] (JJ) imidazopyridinyl,

[1978] (KK) isothiazolyl,

[1979] (LL) naphthyridinyl,

[1980] (MM) cinnolinyl,

[1981] (NN) carbazolyl,

[1982] (OO) β-carbolinyl,

[1983] (PP) isochromanyl,

[1984] (QQ) chromanyl,

[1985] (RR) furazanyl,

[1986] (SS) tetrahydroisoquinoline,

[1987] (TT) isoindolinyl,

[1988] (UU) isobenzotetrahydrofuranyl,

[1989] (VV) isobenzotetrahydrothienyl,

[1990] (WW) isobenzothiophenyl,

[1991] (XX) benzoxazolyl, or

[1992] (YY) pyridopyridinyl,

[1993] where the R_(1-heteroaryl) group is bonded to —(CH₂)₀₋₃- by anyring atom of the parentR_(N-heteroaryl group substituted by hydrogen such that the new bond to the R)_(1-heteroaryl) group replaces the hydrogen atom and its bond, whereheteroaryl is unsubstituted or substituted with one or two:

[1994] (1) C₁-C₃ alkyl,

[1995] (2) —CF₃,

[1996] (3) —F, Cl, —Br, or —I,

[1997] (4) C₁-C₃ alkoxy,

[1998] (5) —0—CF₃,

[1999] (6) —NH₂,

[2000] (7) —OH, or

[2001] (8) —C≡N,

[2002] with the proviso that when n₁ is zero R_(1-heteroaryl) is notbonded to the carbon chain by nitrogen, or

[2003] (VII) —(CH₂)_(n1)-(R_(1-heterocycle)) where n₁ is as definedabove and R_(1 heterocycle) is:

[2004] (A) morpholinyl,

[2005] (B) thiomorpholinyl,

[2006] (C) thiomorpholinyl S-oxide,

[2007] (D) thiomorpholinyl S,S-dioxide,

[2008] (E) piperazinyl,

[2009] (F) hornopiperazinyl,

[2010] (G) pyrrolidinyl,

[2011] (H) pyrrolinyl,

[2012] (I) tetrahydropyranyl,

[2013] (J) piperidinyl,

[2014] (K) tetrahydroflranyl, or

[2015] (L) tetrahydrothiophenyl,

[2016] where the R_(1-heterocycle) group is bonded by any atom of theparent R_(1-heterocycle) group substituted by hydrogen such that the newbond to the R_(1-heteroaryl) group replaces the hydrogen atom and itsbond, where heterocycle is unsubstituted or substituted with one or two:

[2017] (1) ═O,

[2018] (2) C₁-C₃ alkyl,

[2019] (3) —CF₃,

[2020] (4) —F, Cl, —Br and —I,

[2021] (5) C₁-C₃ alkoxy,

[2022] (6) —O—CF₃,

[2023] (7) —NH₂,

[2024] (8)—OH, or

[2025] (9) —C≡N,

[2026] with the proviso that when n₁ is zero R_(1-heterocycle) is notbonded to the carbon chain by nitrogen. Typically, R₁ is (V)—(CH₂)₀₋₁(R_(1-aryl)) or (VI) —(CH₂)_(n1)-(R_(1-heteroaryl)). It ispreferred that R₁ is (V) —(CH₂)-(R_(1-aryl)) or (VI)—(CH₂)-(R_(1-heteroaryl)). It is more preferred that R₁ is—(CH₂)-(R_(1-aryl)) where R_(1-aryl) is phenyl. It is even morepreferred that R₁ is —(CH₂)-(R_(1-aryl)) where R_(1-aryl) is phenylsubstituted with two —F. It is most preferred that the —F substitutionis 3,5 on the phenyl ring.

[2027] When R₁ is R_(1-heteroaryl) or R_(1-heterocycle) the bond fromthe R_(1-heteroaryl) or R_(1-heterocycle) group to the —(CH₂)_(n1)-group can be from any ring atom which has an available valence providedthat such bond does not result in formation of a charged species orunstable valence. This means that the R_(1-heteroaryl) orR_(1-heterocycle) group is bonded to —(CH₂)_(n1)-by any ring atom of theparent R_(1-heteroaryl) or R_(1-heterocycle) group which was substitutedby hydrogen such that the new bond to the R_(1-heteroaryl) orR_(1-heterocycle) group replaces the hydrogen atom and its bond.

[2028] The first step of the process is to protect the free amino groupof the (S)-amino acid (I) with an amino protecting group to produce the(S)-protected amino acid (II) by methods well known to those skilled inthe art. Amino protecting groups are well known to those skilled in theart. See for example, “Protecting Groups in Organic Synthesis”, JohnWiley and sons, New York, N.Y., 2nd ed., 1991, Chapter 7; “ProtectingGroups in Organic Chemistry”, Plenum Press, New York, N.Y., 1973,Chapter 2. The function of the amino protecting group is to protect thefree amino functionality (—NH₂) during subsequent reactions on the(S)-amino acid (I) which would not proceed well either because the aminogroup would react and be finctionalized in a way that is inconsistentwith its need to be free for subsequent reactions or the free aminogroup would interfere in the reaction. When the amino protecting groupis no longer needed, it is removed by methods well known to thoseskilled in the art. By definition the amino protecting group must bereadily removable as is known to those skilled in the art by methodswell known to those skilled in the art. Suitable amino PROTECTING GROUPsinclude t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl,phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl,4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-ethoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1, I -diphenyleth- 1 -yloxycarbonyl, 1 ,1-diphenylprop-1 -yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobomyloxycarbonyl, -phenyl-C(═N)-H, and 1-piperidyloxycarbonyl. It ispreferred that the protecting group be t-butoxycarbonyl (BOC) andbenzyloxycarbonyl (CBZ), it is more preferred that the protecting groupbe t-butoxycarbonyl. One skilled in the art will understand thepreferred methods of introducing a t-butoxycarbonyl or benzyloxycarbonylprotecting group and may additionally consult T.W. Green and P. G. M.Wuts in “Protective Groups in Organic Chemistry”, John Wiley and Sons,2nd ed., 1991, at 327-335 for guidance.

[2029] The (S)-protected amino acid (II) is transformed to thecorresponding (S)-protected amide compound (III) by means well known tothose skilled in the art for the production of an amide from acarboxylic acid and an amine or hydroxylamine. The means and reactionconditions for producing the (S)-protected amide compound (III) include,for example, the use of a coupling agent such as, for example,dicyclohexylcarbodiimide, 1,1-carbonyldiumidazole, POCl₃, TiCl₄, SO₂ClF,benzotriazol-1-yl diethyl phosphate, or N, N, N′,N′-tetramethyl(succinimido)uronium tetrafluoroborate in the presence ofan amine or hydroxylamine. 1,1-Carbonyldiimidazole is a preferredcoupling agent and N-methyl-O-methylhydroxylamine is a preferredhydroxylamine. The reaction is carried out for a period of time between1 hour and 3 days at temperatures ranging from −78° to elevatedtemperature up to the reflux point of the solvent employed. It ispreferred to conduct the reaction between 0° and 50°.

[2030] The (S)-protected amide compound (III) is then reduced by meanswell known to those skilled in the art for reduction of a amide to thecorresponding aldehyde, affording the corresponding aldehyde (IV). Themeans and reaction conditions for reducing the (S)-protected amidecompound (III) to the corresponding aldehyde (IV) include, for example,sodium borohydride, lithium borohydride, borane, diisobutylaluminumhydride, and lithium aluminium hydride. Lithium aluminium hydride is thepreferred reducing agent. The reductions are carried out for a period oftime between 1 hour and 3 days at temperatures ranging from −78° to roomtemperature. It is preferred to conduct the reduction between −20° androom temperature. The preferred combination of reducing agents andreaction conditions needed are known to those skilled in the art, seefor example, Larock, R. C. in Comprehensive Organic Transformations, VCHPublishers, 1989.

[2031] The aldehyde (IV) is transformed to the corresponding olefin (V)by means known to those skilled in the art. An example of such areaction is the reaction of the aldehyde (IV) with a phosphorous ylideto produce the desired olefin. Such phosphorous ylides includemethyltriphenylphosphonium bromide. Reaction conditions includetemperatures ranging from −100° up to the reflux temperature of thesolvent employed; preferred temperature ranges are between −100° and 0°.

[2032] Peracid epoxidation of the olefin (V) affords the epoxide (VI).Other methods for the conversion of an olefin to an epoxide are known tothose skilled in the art. The means for producing the epoxide (VI)include, for example, the use of a peracid such as, for example,peracetic acid, perbenzoic, trifluoroperacetic acid,3,5-dinitroperoxybenzoic acid, and m-chloroperbenzoic acid.

[2033] The epoxide (VI) is then reacted with the appropriate amide (VII)by means known to those skilled in the art which opens the epoxide toproduce the desired corresponding protected alcohol (VIII). Reaction ofthe epoxide (VI) with the amide (VII) produces a mixture of enantiomers.This enantiomeric mixture is then separated by means known to thoseskilled in the art such as selective low-temperature recrystallizationor chromatographic separation, most preferably by HPLC, employingcommercially available chiral columns. The enantiomer that is used inthe remainder of the process of CHART A is the (S,S, R)-alcohol (VIII).

[2034] The protected-alcohol (VIII) is transformed to the correspondingprotected lactone (IX) by means known to those skilled in the art. Apreferred means is by reaction with an acid catalyst, for example, butnot limited to, p-toluenesulfonic acid and the like. Reactions areconducted at temperatures ranging from −78° up to the reflux temperatureof the solvent employed; preferred temperature ranges are between 0° and50°.

[2035] The amine moiety or the protected lactone (IX) is deprotected tothe corresponding amine (X) by means known to those skilled in the artfor removal of amine protecting group. Suitable means for removal of theamine protecting group depends on the nature of the protecting group.Those skilled in the art, knowing the nature of a specific protectinggroup, know which reagent is preferable for its removal. For example, itis preferred to remove the preferred protecting group, BOC, bydissolving the protected lactone (IX) in a trifluoroaceticacid/dichloromethane mixture. When complete, the solvents are removedunder reduced pressure to give the corresponding lactone (as thecorresponding salt, i.e. trifluoroacetic acid salt) which is usedwithout further purification. However, if desired, the lactone can bepurified further by means well known to those skilled in the art, suchas for example, recrystallization. Further, if the non-salt form isdesired that also can be obtained by means known to those skilled in theart, such as for example, preparing the free base amine via treatment ofthe salt with mild basic conditions. Additional BOC deprotectionconditions and deprotection conditions for other protecting groups canbe found in T.W. Green and P.G.M. Wuts in “Protective Groups in OrganicChemistry”, John Wiley and Sons, 1991, p. 309 and following. Chemicallysuitable salts include trifluoroacetate, and the anion of mineral acidssuch as chloride, sulfate, phosphate; preferred is trifluoroacetate.

[2036] The amine (X) is then reacted with an appropriatelysubstituted-amide-forming- agent such as anhydride, acyl halide, or acidof the formula (R_(N-1)-X_(N))₂O or R_(N-1)-X_(N)-X₂ or R_(N-1)-X_(N)—OHby nitrogen-acylation means known to those skilled in the art to producethe corresponding lactone (XI). Nitrogen acylation conditions forreaction of the amine (X) with an amide forming agent to produce thecorresponding lactone (XI) are known to those skilled in the art and canbe found in R. C. Larock in Comprehensive Organic Transformations, VCHPublishers, 1989, p. 981, 979, and 972. R_(N) includes:

[2037] (I) R_(N-1)X_(N)- where X_(N) is:

[2038] (A) —CO—,

[2039] (B) —SO₂—,

[2040] (C) —(CR′R″) 1₆ where R′ and R″ are the same or different and are—H or C₁-C₄ alkyl,

[2041] (D) —CO—(CR′R″)₁₋₆-X_(N-1) where X_(N-1) is —O—, —S—and —NR′R″-and where R′ and R″ are as defined above,

[2042] (E) a single bond;

[2043] where R_(N-1) is:

[2044] (A) R_(N-aryl) where R_(N-aryl) is phenyl, 1-naphthyl and2-naphthyl unsubstituted or substituted with one, two, three or four ofthe following substituents which can be the same or different and are:

[2045] (1) C₁-C₆ alkyl,

[2046] (2) —F, —Cl, —Br, or —I,

[2047] (3) —OH,

[2048] (4) —NO₂,

[2049] (5)—CO—OH,

[2050] (6) —C≡N,

[2051] (7) —CO—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are:

[2052] (a) —H,

[2053] (b) —C₁-C₆ alkyl unsubstituted or substituted with one

[2054] (i) —OH, or

[2055] (ii) —NH₂,

[2056] (c) —C₁-C₆ alkyl unsubstituted or substituted with one to three—F, —Cl, —Br, or —I,

[2057] (d) —C₃-C₇ cycloalkyl,

[2058] (e) -(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[2059] (f) -(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[2060] (g) -C₁-C₆ alkenyl with one or two double bonds,

[2061] (h) -C₁-C₆ alkynyl with one or two triple bonds,

[2062] (i) -C₁-C₆ alkyl chain with one double bond and one triple bond,

[2063] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[2064] (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above,

[2065] (8) —CO—(C₃-C₁₂ alkyl),

[2066] (9) —CO—(C₃-C₆ cycloalkyl),

[2067] (10) —CO-R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove,

[2068] (11) —CO-R_(1-heterocycle) where R_(1-heterocycle) is as definedabove,

[2069] (12) —CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with one or two C₁-C₃ alkyl,

[2070] (13) —CO—O—R_(N-5) where R_(N-5) is:

[2071] (a) C₁-C₆ alkyl, or

[2072] (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[2073] (14) —SO₂-NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are asdefined above,

[2074] (15) —SO—(C₁-C₈ alkyl),

[2075] (16) —SO₂(C₃-C₁₂ alkyl),

[2076] (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,

[2077] (18) —NH—CO—N(C₁-C₃ alkyl)₂,

[2078] (19) —N—CS—N(C₁-C₃ alkyl)₂,

[2079] (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as definedabove,

[2080] (21) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) can be the same ordifferent and are as defined above,

[2081] (22) —R_(N-4) where R_(N-4) is as defined above,

[2082] (23) —O—CO—(C₁-C₆ alkyl),

[2083] (24) —O—CO—N(C₁-C₃ alkyl)₂,

[2084] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[2085] (26) —O—(C₁-C₆ alkyl),

[2086] (27) —O—(C₂-C₅ alkyl)-COOH,

[2087] (28) —S—(C₁-C₆ alkyl),

[2088] (29) C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3, 4, or5—F,

[2089] (30) —O—(C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3,4, or 5 —F, or

[2090] (31) —O-φ,

[2091] (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is:

[2092] (A) pyridinyl,

[2093] (B) pyrimidinyl,

[2094] (C) quinolinyl,

[2095] (D) indenyl,

[2096] (E) indanyl,

[2097] (F) benzothiophenyl,

[2098] (G) indolyl,

[2099] (H) indolinyl,

[2100] (I) pyridazinyl,

[2101] (J) pyrazinyl,

[2102] (K) isoindolyl,

[2103] (L) isoquinolyl,

[2104] (M) quinazolinyl,

[2105] (N) quinoxalinyl,

[2106] (O) phthalazinyl,

[2107] (P) imidazolyl,

[2108] (Q) isoxazolyl,

[2109] (R) pyrazolyl,

[2110] (S) oxazolyl,

[2111] (T) thiazolyl,

[2112] (U) indolizinyl,

[2113] (V) indazolyl,

[2114] (W) benzothiazolyl,

[2115] (X) benzimidazolyl,

[2116] (Y) benzofuranyl,

[2117] (Z) furanyl,

[2118] (AA) thienyl,

[2119] (BB) pyrrolyl,

[2120] (CC) oxadiazolyl,

[2121] (DD) thiadiazolyl,

[2122] (EE) triazolyl,

[2123] (FF) tetrazolyl,

[2124] (GG) 1,4-benzodioxan

[2125] (HH) purinyl,

[2126] (II) oxazolopyridinyl,

[2127] (JJ) imidazopyridinyl,

[2128] (KK) isothiazolyl,

[2129] (LL) naphthyridinyl,

[2130] (MM) cinnolinyl,

[2131] (NN) carbazolyl,

[2132] (OO) β-carbolinyl,

[2133] (PP) isochromanyl,

[2134] (QQ) chromanyl,

[2135] (RR) furazanyl,

[2136] (SS) tetrahydroisoquinoline,

[2137] (TT) isoindolinyl,

[2138] (UU) isobenzotetrahydrofuranyl,

[2139] (VV) isobenzotetrahydrothienyl,

[2140] (WW) isobenzothiophenyl,

[2141] (XX) benzoxazolyl, or

[2142] (YY) pyridopyridinyl,

[2143] where the R_(N-heteroaryl) group is bonded by any atom of theparent R_(N-heteroaryl) group substituted by hydrogen such that the newbond to the R_(N-heteroaryl) group replaces the hydrogen atom and itsbond, where heteroaryl is unsubstituted or substituted with one or two:

[2144] (1) C₁-C₆ alkyl,

[2145] (2) —F, —Cl, —Br, or —I,

[2146] (3) —OH,

[2147] (4) —NO₂,

[2148] (5) —CO—OH,

[2149] (6) —CN,

[2150] (7) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are:

[2151] (a) —H,

[2152] (b) —C₁-C₆ alkyl unsubstituted or substituted with one

[2153] (i) —OH, or

[2154] (ii) —NH₂,

[2155] (c) —C₁-C₆ alkyl unsubstituted or substituted with 1, 2, or 3 —F,—Cl, —Br, or —I,

[2156] (d) —C₃-C₇ cycloalkyl,

[2157] (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl),

[2158] (f) —(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl),

[2159] (g) —C₁-C₆ alkenyl with one or two double bonds,

[2160] (h) —C₁-C₆ alkynyl with one or two triple bonds,

[2161] (i) —C₁-C₆ alkyl chain with one double bond and one triple bond,

[2162] (j) —R_(1-aryl) where R_(1-aryl) is as defined above, or

[2163] (k) R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above,

[2164] (8) —CO—(C₃-C₁₂ alkyl),

[2165] (9) —CO—(C₃-C₆ cycloalkyl),

[2166] (10) —CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as definedabove,

[2167] (11) —CO—R_(1-heterocycle) where R_(1-heterocycle) is as definedabove,

[2168] (12) —CO—RN—₄ where R_(N-4) is morpholinyl, thiomorpholinyl,piperazinyl, piperidinyl or pyrrolidinyl where each group isunsubstituted or substituted with one or two C₁-C₃ alkyl,

[2169] (13) —CO—O—R_(N-5) where R_(N-5) is:

[2170] (a) C₁-C₆ alkyl, or

[2171] (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as defined above,

[2172] (14) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are as definedabove,

[2173] (15) —SO—(C₁-C₈ alkyl),

[2174] (16) —SO₂(C₃-C₁₂ alkyl),

[2175] (17) —NH—CO—O—R_(N-5) where R_(N-5) is as defined above,

[2176] (18) —NH—CO—N(C₁-C₃ alkyl)₂,

[2177] (19) —N—CS—N(C₁-C₃ alkyl)₂,

[2178] (20) —N(C₁-C₃ alkyl)-CO—RN₅ where R_(N-5) is as defined above,

[2179] (21) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) can be the same ordifferent and are as defined above,

[2180] (22) —R_(N-4) where R_(N-4) is as defined above,

[2181] (23) —O—CO—(C₁-C₆ alkyl),

[2182] (24) —O—CO—N(C₁-C₃ alkyl)₂,

[2183] (25) —O—CS—N(C₁-C₃ alkyl)₂,

[2184] (26) —O—(C₁-C₆ alkyl),

[2185] (27) —O—(C₂-C₅ alkyl)-COOH, or

[2186] (28) —S—(C₁-C₆ alkyl),

[2187] (C) —R_(N-aryl)—R_(N-aryl) where —R_(N-aryl) is as defined above,

[2188] (D) —R_(N-aryl)—R_(N-heteroaryl) where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[2189] (E) —R_(N-heteroaryl)R_(N-aryl)where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above,

[2190] (F) —R_(N-heteroaryl)-R_(N-heteroaryl) where R_(N-heteroaryl) isas defined above,

[2191] (G) —R_(N-aryl)-O—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[2192] (H) —R_(N-aryl)—S—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[2193] (I) —R_(N-heteroaryl)-OR_(N-heteroaryl) where R_(N-heteroaryl) isas defined above,

[2194] (J) —R_(N-heteroaryl)—SR_(N-heteroaryl) where R_(N-heteroaryl) isas defined above,

[2195] (K) —R_(N-aryl)—CO—R_(N-aryl) where —R_(N-aryl)is as definedabove,

[2196] (L) —R_(N-aryl)—CO—R_(N-heteroaryl) where —R_(N-aryl) andR_(N-heteroayl) are as defined above,

[2197] (M) —R_(N-aryl)—SO₂—R_(N-aryl) where —R_(N-aryl) is as definedabove,

[2198] (N) —R_(N-heteroaryl-CO—RN-heteroaryl where R) _(N-heteroaryl) isas defined above,

[2199] (O) —R_(N-heteroaryl)—SO₂—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above,

[2200] (P) —R_(N-aryl)-O—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[2201] (Q) —R_(N-aryl)—S—(C₁-C₈ alkyl)-φ where R_(N-aryl) is as definedabove,

[2202] (R) —RN-heteroary-O-(C₁-C₈ alkyl)-φ where R_(N-heteroaryl) is asdefined above, or

[2203] (S) —R_(N-heteroaryl)S-(C₁-C₈ alkyl)-φ where R_(N-heteroaryl) isas defined above,

[2204] (II) A—X_(N)- where X_(N) is —CO—,

[2205] wherein A is

[2206] (A) —T-E—(Q)_(m′),

[2207] (1) where —T is

[2208] where

[2209] (a) x=1 when y=1 and x=2 when y=0,

[2210] (b) m is 0, 1, 2 or 3,

[2211] (c) the values of x and y vary independently on each carbon whenm is 2 and 3, and

[2212] (d) R″ varies independently on each carbon and is H, (C₁-C₂)alkyl, phenyl, or phenyl(C₁-C₃)alkyl;

[2213] (2) -E is

[2214] (a) C₁-C₅ alkyl, but only if m′ does not equal 0,

[2215] (b) methylthioxy(C₂-C₄)alkyl,

[2216] (c) an aryl group having 5 to 7 atoms when monocyclic or having 8to 12 atoms when fused,

[2217] (d) a heterocyclic group having 5 to 7 atoms when monocyclic orhaving 8 to 12 atoms when fused,

[2218] (e) a mono or fused ring cycloalkyl group having 5 to 10 carbonatoms,

[2219] (f) biphenyl,

[2220] (g) diphenyl ether,

[2221] (h) diphenylketone,

[2222] (i) phenyl(C₁-C₈)alkyloxyphenyl, or

[2223] (j) C₁-C₆ alkoxy;

[2224] (3) —Q is

[2225] (a) C₁-C₃ alkyl,

[2226] (b) C₁-C₃ alkoxy,

[2227] (c) C₁-C₃ alkylthioxy,

[2228] (d) C₁-C₆ alkylacylamino,

[2229] (e) C₁-C₆ alkylacyloxy,

[2230] (f) amido (including primary, C₁-C₆ alkyl and phenyl secondaryand tertiary amino moieties),

[2231] (g) C₁-C₆ alkylamino

[2232] (h) phenylamino,

[2233] (i) carbamyl (including C₁-C₆ alkyl and phenyl amides andesters),

[2234] (j) carboxyl (including C₁-C₆ alkyl and phenyl esters),

[2235] (k) carboxy(C₂-C₅)alkoxy,

[2236] (l) carboxy(C₂-C₅)alkylthioxy,

[2237] (m) heterocyclylacyl,

[2238] (n) heteroarylacyl, or

[2239] (o) hydroxyl;

[2240] (4) m′is 0, 1, 2 or 3;

[2241] (B) -E(Q)_(m″) wherein E and —Q are as defined as above and m″ is0, 1, 2, or 3;

[2242] (C) —T-E wherein -E and —Q are as defined as above; or

[2243] (D) -E wherein -E is as defined as above;

[2244] (III) —CO—(C₁-C₆ alkyl) where alkyl is unsubstituted orsubstituted with one or two:

[2245] (A) —OH,

[2246] (B) —C₁-C₆ alkoxy,

[2247] (C) —C₁-C₆ thioalkoxy,

[2248] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or -φ,

[2249] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[2250] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[2251] (G) —SO₂—(C₁-C₈ alkyl),

[2252] (H) —SO2—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[2253] (I) —NH—CO—(C₁-C₆ alkyl),

[2254] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[2255] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[2256] (L) —R_(N-4) where R_(N-4) is as defined above,

[2257] (M) —O—CO—(C₁-C₆ alkyl),

[2258] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) is the same ordifferent and are as defined above, or

[2259] (O) —O—(C₁-C₅ alkyl)-COOH,

[2260] (IV) —CO—(C₁-C₃ alkyl)-O—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with one or two

[2261] (A) —OH,

[2262] (B) —C₁-C₆ alkoxy,

[2263] (C) —C₁-C₆ thioalkoxy,

[2264] (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or -φ,

[2265] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[2266] (F) —CO—R_(N-4) where R_(N-4) is as defined above,

[2267] (G) —SO₂—(C₁-C₈ alkyl),

[2268] (H) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[2269] (I) —NH—CO—(C₁-C₆ alkyl),

[2270] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[2271] (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[2272] (L) —R_(N-4) where R_(N-4) is as defined above,

[2273] (M) —O—CO—(C₁-C₆ alkyl),

[2274] (N) —O—CO—NRN8R_(N-8) where the R_(N-8) are the same or differentand are as defined above, or

[2275] (O) —O—(C₁-C₅ alkyl)-COOH,

[2276] (V) —CO—(C₁-C₃ alkyl)-S—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with one or two

[2277] (A) —OH,

[2278] (B) —C₁-C₆ alkoxy,

[2279] (C) —C₁-C₆ thioalkoxy,

[2280] (D) CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or

[2281] (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[2282] (F) —CO—RN₄ where R_(N-4) is as defined above,

[2283] (G) —SO₂—(C₁-C₈ alkyl),

[2284] (H) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[2285] (I) —NH—CO—(C₁-C₆ alkyl),

[2286] (J) —NH—CO—O—R_(N-8) where R_(N-8) is as defined above,

[2287] (K) —NR_(N-2) R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above,

[2288] (L) —R_(N-4) where R_(N-4) is as defined above,

[2289] (M) —O—CO—(C₁-C₆ alkyl),

[2290] (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) are the same ordifferent and are as defined above, or

[2291] (O) —O—(C₁-C₅ alkyl)-COOH,

[2292] (VI)—CO—CH(—(CH₂)0-2—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl)) whereR_(N-aryl) and R_(N-heteroaryl) are as defined above, where R_(N-1O) is:

[2293] (A) —H,

[2294] (B) C₁-C₆ alkyl,

[2295] (C) C₃-C₇ cycloalkyl,

[2296] (D) C₂-C₆ alkenyl with one double bond,

[2297] (E) C₂-C₆ alkynyl with one triple bond,

[2298] (F) R_(1-aryl) where R_(1-aryl) is as defined above, or

[2299] (G) R_(N-heteroaryl) where R_(N-heteroaryl) is as defined above.

[2300] It is preferred that R_(N) is R_(N-1)-X_(N)- where X_(N) is —CO—,where RN-, is R_(N-aryl) where R_(N-aryl) is phenyl substituted with one—CO—NR_(N-2) R_(N-3) where the substitution on phenyl is 1,3-,

[2301] R_(N-1)-X_(N)- where X_(N) is -CO—, where R_(N-1) is R_(N-aryl)where R_(N-aryl) is phenyl substituted with one C₁ alkyl and with one—CO—NR_(N-2)R_(N-3)where the substitution on the phenyl is 1,3,5-, or

[2302] R_(N-1)-X_(N)- where X_(N) is —CO—, where R_(N-1) isR_(N-heteroaryl) where R_(N-heteroaryl) is substituted with one—CO—NR_(N-2)R_(N-3). It is further preferred that R_(N-2) and R_(N-3)are the same and are C₃ alkyl.

[2303] It is further preferred that:

[2304] R_(N-1)-X_(N)- where X_(N) is —CO—, where R_(N-1) is R_(N-aryl)where R_(N-aryl) is phenyl substituted with one —CO—NR_(N-2)R_(N-3)wherethe substitution on phenyl is 1,3-,

[2305] R_(N-1)-X_(N)- where X_(N) is—CO—, where R_(N-1) is R_(N-aryl)where R_(N-aryl) is phenyl substituted with one C₁ alkyl and with one—CO—NR_(N-2)R_(N-3) where the substitution on the phenylis 1,3,5-.

[2306] It is preferred that X_(N) is (A) —CO— and (B) —SO₂—; it is morepreferred that X_(N) be —CO—.

[2307] The nitrogen-acylation of primary amines to produce secondaryamides is one of the oldest known reactions. The amide forming agents,(R_(N-1)-X_(N))₂O or R_(N-1)-X_(N)-X₂ orR_(N-1)-X_(N—OH are known to those skilled in the art and are commercially available or can be readily prepared from known starting materials by methods known in the literature. X)₂ includes —Cl, —Br; it is preferred that X₂ is —Cl. It is preferred touse an isophthalic acid acylating agent of the formulaR_(N-2)R_(N-3)N—CO—φ—CO— or a methylisophthalic acid acylating agentR_(N-2)R_(N-3)N—CO—(CH₃—)φ—CO— where the substitution is5-methyl-1,3-isophthalic acid. The more preferred5-methyl-1,3-isophthalic acid is3-[(N,N-dipropylamino)carbonyl]-5-methylbenzoic acid. These compoundsare preferably prepared as set forth as follows. An ester, preferablythe methyl ester of isophthalate or methyl 5-methyl-1,3-isophthalate isdissolved in a THF/DMF mixture. 1,1′-Carbonyldiimidazole is then addedat 0-100°. Next the desired amine (H-NR_(N-2)RN3) is added. Afterstirring at 0-100° the reaction mixture is partitioned between asaturated aqueous solution with a pH of 3 to 9 and a water immiscibleorganic solvent. The aqueous layer is separated and extracted twice morewith the organic solvent. The organic extracts are combined and thenwashed with an aqueous solution and dried. Filtration of the dryingagent and removal of solvents by reduced pressure gives crude ester ofthe desired RN-₂RN-₃N-CO-+-CO-O-CH₃ or a methylisophthalic acidacylating agent RN₂RN₃N-CO-(CH₃-)+-CO-O-CH₃. Purification of the estercan be achieved via chromatography on silica gel eluting with a suitablesolvent The isophthalate ester or methylisophthalate ester of themono-alkyl or di-alkyl amide is then treated with an aqueous solution ofbase such as alkali hydroxide in a minimum amount of THF/methanol/waterand stirred at 20-70° with monitoring. The solvents are removed underreduced pressure and subsequently partitioned between water and a waterimmiscible organic solvent. The aqueous phase is separated and extractedonce more with a water immiscible organic solvent. The aqueous phase wasthen acidified to pH <3. The mixture obtained is then extracted threetimes with ethyl acetate. These combined organic extracts are thendried. The drying agent is removed by filtration and the organic solventremove under reduced pressure to gave crude product. The crude mono- ordi-alkyl amide isophthalate/methylisophthalate is used as such in thenext reaction with the amine (X) to produce the lactone (XI).

[2308] When it is desired to produce a primary amide, R_(N-2) andR_(N-3) are both -H, the following procedure is preferred. An ester ofisophthalate or methyl 5-methyl-1,3- isophthalate is dissolved in aTHF/DMF mixture. CDI is then added at 0-100°. Ammonia gas is thenbubbled into the mixture with monitoring. The reaction is cooled to 0°for the duration of the ammonia addition. The reaction is left stirringunder a balloon of ammonia at 0100° with monitoring. The reaction ispartitioned between a aqueous solution with a pH of 3 to 9 and a waterimmiscible organic solvent. The phases are separated and the aqueousphase is extracted twice more with a water immiscible organic solvent.The organic extracts are washed with an aqueous solution and dried.Removal of solvents under reduced pressure gives crude ester of thedesired H₂N-CO-+-CO- O(Alkyl) or a methylisophthalic acid acylatingagent H₂N-CO-(CH₃-)+-CO-O(Alkyl). Purification of the crude ester can beachieved via chromatography on silica gel eluting withisopropanol/chlorofonn. The isophthalate ester or methylisophthalateester of the primary amide is then treated with an aqueous solution ofbase such as alkali hydroxide in a minimum amount of THF/methanol/waterand stirred at 0-100° with monitoring. The solvents are removed underreduced pressure and subsequently partitioned between water and a waterimmiscible organic solvent. The aqueous phase is separated and extractedonce more with a water immiscible organic solvent. The aqueous phase isthen acidified until pH <3. The mixture obtained is then extracted threetimes with a water immiscible organic solvent. These combined organicextracts are dried and the organic solvent removed under reducedpressure to gave crude product. The primary amideisophthalate/methylisophthalate is used as such in the next reactionwith (X) to produce (XI)

[2309] When it is desired that the amine be cyclized to be a group suchas morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl, etc thefollowing procedure is followed. An ester of isophthalate or methyl5-methyl-1,3-isophthalate is dissolved in a suitable organic solvent anda catalytic amount or DMF is added. The mixture is cooled to -200 tobelow rt and then oxalyl chloride is added. The mixture is stirred withmonitoring and the solvents removed under reduced pressure. The acidchloride is left under vacuum overnight. The crude acid chloride isdissolved in a suitable organic solvent and cooled to -20° to below rtbefore the addition of the cyclic amine and N-methyl piperidine. Thereaction mixture is stirred at -20° to below rt with monitoring beforethe solvents are removed. The residue is diluted with water and waterimmiscible organic solvent and the phases are separated. The aqueousphase is extracted twice more with water immiscible organic solvent, andthe combined organic extracts are washed with an aqueous solution anddried. Removal of solvents under reduced pressure gives the crudeproduct. The crude cyclicamide is then treated with an aqueous base suchas alkali hydroxide a minimum amount of THF/methanol/water and stirredovernight at 0-100°. The solvents are removed under reduced pressure andsubsequently partitioned between water and a water immiscible organicsolvent. The aqueous phase is extracted once more with a waterimmiscible organic solvent. Removal of water from the aqueous phaseunder reduced pressure gives the desired cyclic amide product.

[2310] The lactone (XI) may then be reacted with the appropriatelysubstituted C- terminal amine, Rc-NH2 by means known to those skilled inthe art which opens the lactone to produce the desired hydroxyethyleneend product (XII). The substituted C- terminal amines, Rc-NH2 of thisinvention are commercially available or are known to those skilled inthe art and can be readily prepared from known compounds. Rc includes:

[2311] (I) -(C₁-Clo)alkyl-KI-₃ in which:

[2312] (A) the alkyl chain is unsubstituted or substituted with one -OH,(B) the alkyl chain is unsubstituted or substituted with one C₁-C₆alkoxy unsubstituted or substituted with 1-5 -F, (C) the alkyl chain isunsubstituted or substituted with one O0, (D) the alkyl chain isunsubstituted or substituted with 1, 2, 3, 4 or 5-F, (E) the alkyl chainis unsubstituted or substituted with a combination of up to three atomsof oxygen and sulfur each such atom replacing one carbon, (F) each K is:(1) H,

[2313] (2) C₁-C₃ alkyl, (3) C₁-C₃ alkoxy, (4) C₁-C₃ alkylthioxy, (5)C₁-C₆ alkylacylamino, (6) C₁-C₆ alkylacyloxy, (7) amido (8) C₁-C₆alkylamino (9) phenylamino, (10) carbamyl (1 1) carboxyl (12)carboxy(C₂-C₅)alkoxy, (13) carboxy(C₂-C5)alkylthioxy, (14)heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted orsubstituted with C₁-C₆ alkyl, (17) hydroxyl, or (18) carboxyl methylester; (II)-(CH₂)₀₋₃-J-[(-(CH₂)₀₋₃-K]II₃ where K is as defined above andJ is:

[2314] (A) a 5 to 7 atom monocyclic aryl group, (B) a 8 to 12 atommulticyclic aryl group, (C) a 5 to 7 atom heterocyclic group, (D) a 8 to12 atom multicyclic heterocyclic group, or (E) a 5 to 10 atom monocyclicor multicyclic cycloalkyl group; (III) -(CH₂)₀₋₃-(C₃-C₇) cycloalkylwhere cycloalkyl can be unsubstituted or substituted with one, two orthree (A) C₁-C₃ alkyl unsubstituted or substituted with 1, 2, 3, or 4-F, -Cl, -Br, or -I, (B) -CO-OH, (C) -CO-O-(C₁-C₄ alkyl), (D)-OH, or (E)C₁-C₆ alkoxy, (IV) -(CH₂)₂-₆-OH, (V) -(CRC ,RC-y)0-4—Rc-al where Rc-,and Rc-y are -H, C₁-C₄ alkyl and ¢- and Rc-ary is the same as RN-aS,yi(VI) -(CH2)04—R_(C-heteroaryl) where Pc-heteroaryl is:

[2315] (A) pyridinyl, (B) pyrimidinyl, (C) quinolinyl, (D) indenyl, (E)indanyl, (F) benzothiophenyl, (G) indolyl, (H) indolinyl, (I)pyridazinyl, (J) pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M)quinazolinyl, (N) quinoxalinyl, (0) phthalazinyl, (P) isoxazolyl, (Q)pyrazolyl, (R) indolizinyl, (S) indazolyl, (T) benzothiazolyl, (U)benzimidazolyl, (V) benzofuranyl, (W) fliranyl, (X) thienyl, (Y)pyrrolyl, (Z) oxadiazolyl, (AA) thiadiazolyl, (BB) triazolyl, (CC)tetrazolyl, (DD) 1, 4-benzodioxan (EE) purinyl, (FF) oxazolopyridinyl,(GG) imidazopyridinyl, (HH) isothiazolyl, (II) naphthyridinyl, (JJ)cinnolinyl, (KK) carbazolyl, (LL) P-carbolinyl, (MM) isochromanyl, (NN)chromanyl, (00) furazanyl, (PP) tetrahydroisoquinoline, (QQ)isoindolinyl, (RR) isobenzotetrahydrofuranyl, (SS)isobenzotetrahydrothienyl, (TT) isobenzothiophenyl, (UU) benzoxazolyl,or (VV) pyridopyridinyl, (VI ) -(CH2)0-4—RC-beterocycle whereRc-heterocycle is the same as RI heterocycle, (VIII)-C(Rc,)(Rc₂)-CO-NH-Rc-3 where Rc-I and Rc-2 are the same or differentand are: (A) -H, (B) -C₁-C₆ alkyl, (C) -(C₁-C4 alkyl)-Rcary, whereRc,-al is as defined above for RIarylg (D) -(C₁-C₄ alkyl)-Rcheteroalwhere R_(C-heteroaryl) is as defined above, (E) -(C₁-C₄ alkyl)-Rcheterocycle where R_(C-heterocycle) is as defined above, (F)R_(C-heteroaryl) where RCheteroaryl is as defined above, (G)—R_(C-heterocycle) where R_(C-heterocycle) is as defined above, (H)-(CH₂)₁₄-OH, (I) -(CH₂)1₄—RC₄-(CH₂)1-₄—Rc′-aryl where Rc4 is -O-, -S-,-NH- or -NHRc5- where Rc-5 is C₁-C₆ alkyl, and where Rc,-ary, is asdefined above, (J) -(CH2)1-4—Rc4-(CH2)1-4—R_(C-heteroaryl) where Rc4 andRC-heteroary are as defined above, or (K) —RC-aryl where RC,-aryl is asdefined above, and where Rc-3 is: (A) -H,

[2316] (B) -C₁-C₆ alkyl, (C) —Rc-′ry] where Rc,-al y is as definedabove, (D) —R_(C-heteroaryl) where RC-h,te,oaayl is as defined above,(E) —R_(C-heterocycle) where RC-beterocycle is as defined above, (F)-(C₁-C₄ alkyl)-Rcary, where Rc,aly is as defined above, (G) -(C₁-C₄alkyl)-Rcheteroaryl where RC-heteroary is as defined above, or (H) -(CI-C₄ alkyl)-R_(C-heterocycle) where RCheterocycle is as defined above,(IX) -CH(+)₂, (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl orheteroaryl ring where heteroaryl is as defined above and phenyl andheteroaryl are unsubstituted or substituted with one, two or three:

[2317] (A) C₁-C₃ alkyl, (B) -CF₃, (C) -F, Cl, -Br and -, (D) C₁-C₃alkoxy, (E) -OCF₃, (F) -NH2, (G) -OH, or (H) -C-N, (XI) -CH₂-C=-CH;(XII) -(CH2)01-CHRc-5-(CH2)o-,-+where Rc-5 is:

[2318] (A) -OH, or (B)-CH₂-OH; (XIII) CH(-+)-CO-O(C₁-C₃ alkyl); (XIV)-CH(-CH2-OH)-CH(-OH)-+-NO₂; (XV) -(CH₂)₂-O-(CH₂)₂-OH; (XVI)-CH₂-NH-CH₂-CH(-O-CH₂-CH₃)₂; (XVII) -(C₂-C₈) alkynyl; or (XVIII) -H.Typically, Rc is:

[2319] (I)-C₁-C₈ alkyl, (II) -(CH₂)₀₋₃-(C₃-C₇) cycloalkyl, (III)-(CH₂)₀₋₃-OH, (IV) -(CRc-xRc-y)₀₋₄—RC-ayl, (V) -(CH2)04—Rcheteroaryl,(VI ) -(CH2)04—Rcheterocycleg (VII) -C(Rci)(Rc₂)-CO-NH-Rc-₃, (IX)-cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ringwhere heteroaryl is as defined above and phenyl and heteroaryl areunsubstituted or substituted with one or two:

[2320] (A) C₁-C₃ alkyl, (B) -CF₃, (C) -F, Cl, -Br or -I, (D) C₁-C₃alkoxy, (E) -OCF₃, or (XVI) -H. It is preferred that RC is:

[2321] (II) -(CH₂)₀₋₃-(C₃-C₇) cycloalkyl, (IV) -(CRc-xRc-y)₀₋₄—Rc-ayl,(V) -(CH2)04—Rcheteroaryl, (VI ) -(CH2)04—R_(C-heterocycle), (VII)-C(Rc1)(Rc-₂)-CO-NH-Rc-₃, or (IX) -cyclopentyl or -cyclohexyl ring fusedto a phenyl or heteroaryl ring. It is more preferred that Rc is:

[2322] (IV) -(CRc xRcy)₀₋₄—Rcaryl, (V) -(CH2)04—Rcbeteroaryl, (VI)-(CH2)04—Rcbeterocycle, or (IX) -cyclopentyl or -cyclohexyl ring fusedto a phenyl or heteroaryl ring. It is most preferred that Rc is:

[2323] (IV) —(CR_(C-x)R_(C-y))₀₋₄R_(C-aryl) where R_(C-aryl) is phenyl,

[2324] (V) CH₂—R_(C-heteroaryl),

[2325] (VI) CH₂—R_(C-heterocycle), or

[2326] (IX) -cyclohexyl ring fused to a phenyl ring. Further, it ispreferred that when R_(C) is phenyl, it is substituted in the 3-positionor 3,5-positions.

[2327] Suitable reaction conditions for opening the lactone (XI) toproduce the desired hydroxyethylene end product (XII) include those ofthe AlMe₃-mediated coupling reaction disclosed in the literatureprocedure of S. F. Martin et al., Tetrahedron Lett. 1998, 39, 1517-1520.When the substituted C-terminal amine is a 1-amino-3,5-cis-dimethylcyclohexyldicarboxylate it is preferrably prepared as follows. Todimethyl-5-isophthalate in acetic acid and methanol, is added rhodium inalumina in a high-pressure bottle. The bottle is saturated with hydrogenat 55 psi and shaken for one week of time. The mixture is then filteredthrough a thick layer of celite cake and rinsed with methanol threetimes, the solvents are removed under reduced pressure (with heat) togive a concentrate. The concentrate is triturated with ether andfiltered again to give the desired C-terminal amine. When thesubstituted C-terminal amine is 1-amino-3,5-cis-dimethoxy cyclohexane itis preferably following the general procedure above and makingnon-critical variations but starting wth 3,5-dimethoxyaniline. When thesubstituted C-terminal amine is an aminomethyl group where thesubstituent on the methyl group is an aryl group, for exampleNH₂—CH₂—R_(C-aryl), and NH₂—CH₂—R_(C-aryl) is not commercially availableit is preferrably prepared as follows. A suitable starting material isthe (appropriately substituted) aralkyl compound. The first step isbromination of the alkyl substitutent via methods known to those skilledin the art, see for example R. C. Larock in Comprehensive OrganicTransformations, VCH Publishers, 1989, p. 313. Next the alkyl halide isreacted with azide to produce the aryl-(alkyl)-azide. Last the azide isreduced to the corresponding amine by hydrogen/catalyst to give theC-terminal amine of formula NH₂—CH₂—R_(C-aryl).

[2328] CHART B, as defined within, sets forth a process for productionof the amide (VII). Preparation of the amide (VIII) starts with thereaction of an appropriate amino-indanol (XIV) with an appropriatehaloketone (XII) to afford the hydroxy indane (XV). The amino-indanol(XIV) and haloketone (XII) are well known to those skilled in the art orcan be readily prepared from known compounds by methods well known tothose skilled in the art. The X substituent of the haloketone istypically F, Cl, Br, or I. Preferably X is Cl. For the amino haloketone(XII), R₂ is:

[2329] (I) —H,

[2330] (II) C₁-C₆ alkyl, or

[2331] (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is (C₃-C₆)cycloalkyl, R_(1-aryl)or R_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as definedabove,

[2332] Certain hydroxyethylene compounds of formula (XII) contain acidicfunctionality capable of forming base addition salts. Additionally,certain hydroxyethylene compounds of formula (XII) contain basicfunctionality capable of forming acid addition salts. For example,certain hydroxyethylene compounds of formula (XII) are amines and assuch form salts when reacted with acids. Pharmaceutically acceptablesalts are preferred over the corresponding hydroxyethylene compounds offormula (XII) since they produce compounds which are more water soluble,stable and/or more crystalline. Pharmaceutically acceptable salts areany salt which retains the activity of the parent compound and does notimpart any deleterious or undersirable effect on the subject to whom itis administered and in the context in which it is administered.Pharmaceutically acceptable salts include salts of both inorganic andorganic acids. The preferred pharmaceutically acceptable salts includesalts of the following acids: hydrochloric, hydrobromic, hydroiodic,nitric, sulfuric, phosphoric, citric, methanesulfonic,CH₃-(CH₂)_(n1)—COOH where n₁ is 0 thru 4, HOOC—(CH₂)_(n1)—COOH where nis as defined above, HOOC-CH=CH-COOH, and (p-COOH. Additionally,preferred pharmaceutically acceptable salts include salts of thefollowing bases: triethanolamine, N-methylglucamine, diethanolamine,ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, andcarbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali oralkaline earth metal. For other acceptable salts, see Int. J. Pharm.,33, 201-217 (1986).

[2333] Preferred hydroxyethylene compounds of formula (XII), include,for example,

[2334] N-[(1S, 2S, 4R)-1-(3,5-Difluorobenzyl)-4-(syn, syn)-(3,5dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide,

[2335]6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoicacid,

[2336] 5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoicacid,

[2337]4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyricacid,

[2338]3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionicacid,

[2339]8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoicacid,

[2340] 8-[6-(3,5 -Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoicacid methyl ester,

[2341] N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

[2342]N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide,

[2343]N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

[2344]N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

[2345]N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide,

[2346]N-[1-(S-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

[2347]N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

[2348]N-[1-(5S-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide,

[2349]4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid methyl ester,

[2350] N-[1-(5-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,

[2351] 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,

[2352] 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,

[2353]4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(5)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,

[2354]4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,

[2355] 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,

[2356] 4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,

[2357]4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,

[2358]4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid methyl ester,

[2359]N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

[2360]N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

[2361]N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

[2362]N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,

[2363]N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

[2364]N-[1-(S-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

[2365]N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

[2366] N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

[2367]N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,

[2368] N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,or

[2369] N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide.

[2370] Additional preferred hydroxyethylene compounds of formula (XII)include, for example those of the following formulae:

[2371] Most preferred hydroxyethylene compounds of formula (XII),include, for example,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid.

[2372] 6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoicacid,

[2373]8-[6-(3,5-Difluoro-phenyl)-5-(-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoicacid methyl ester,

[2374]4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid

[2375] 4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5 -(s)-(3-dipropylcarbamoyl-benzoylamnino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid, and

[2376]4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid.

[2377] The hydroxyethylene compounds of formula (XII), andpharmaceutically acceptable salts thereof, are useful for treatinghumans suffering from Alzheimer's disease, for helping prevent or delaythe onset of Alzheimer's disease, for treating patients with MCI (mildcognitive impairment) and preventing or delaying the onset ofAlzheimer's disease in those who would progress from MCI to AD, fortreating Down's syndrome, for treating humans who have HereditaryCerebral Hemorrhage with Amyloidosis of the Dutch-Type, for treatingcerebral amyloid angiopathy and preventing its potential consequences,i.e. single and recurrent lobal hemorrhages, for treating otherdegenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse Lewy body typeAlzheimer's disease. It is preferred the the disease is Alzheimer'sdisease.

[2378] When treating these diseases, the hydroxyethylene compounds offormula (XII) can either be used individually or in combination as isbest for the patient.

[2379] With regard to these diseases the term “treating” means that thehydroxyethylene compounds of formula (XII) can be used in humans withexisting disease. The hydroxyethylene compounds of formula (XII) willnot necessarily cure the patient who has the disease but will delay orslow the progression of the disease thereby giving the individual a moreuseful life span.

[2380] The term “preventing” means that if the compounds of the presentinvention are administered to those who do not now have the disease butwho would normally get the disease or be at increased risk for thedisease, they will not get the disease. In addition, “preventing” alsoincludes delaying the development of the disease in an individual whowill ultimately get the disease or would be at risk for the disease. Bydelaying the onset of the disease, the hydroxyethylene compounds offormula (XII) have prevented the individual from getting the diseaseduring the period in which the individual would normally have gotten thedisease or reduce the rate of development of the disease or some of itseffects but for the administration of the hydroxyethylene compounds offormula (XII) up to the time the individual ultimately gets the disease.Preventing also includes administration of the compounds of theinvention to those individuals thought to be predisposed to the diseasedue to familial history and/or due to the presence of one or morebiological markers for the disease such as a known genetic mutation ofAPP or by analysis of APP cleavage products in body tissues or fluids.

[2381] In treating or preventing the above diseases the hydroxyethylenecompounds of formula (XII) are administered in a therapeuticallyeffective amount. The therapeutically effective amount will varydepending on the particular compound used and the route ofadministration as is known to those skilled in the art.

[2382] In treating a patient with any of the diagnosed above conditionsa physician may administer hydroxyethylenes of formula (XII) immediatelyand continue indefinitely.

[2383] In treating patients who do not at the present have Alzheimer'sdisease, but who are believed to be at substantial risk for Alzheimer'sdisease, the physician should start treatment when the patient firstexperiences early pre-Alzheimer's symptoms such as, memory or cognitiveproblems associated with aging. In addition, there are some patients whomay be diagnosed with Alzheimer's through the detection of the geneticmarker APOE4 or other biological indicators that are predictive forAlzheimer's disease. In these situations, even though the patient doesnot have symptoms of the disease, the administration of thehydroxyethylene compounds of formula (XII) may be started before theyappear and treatment continued indefinitely to prevent or delay theoutset of the disease.

[2384] The hydroxyethylene compounds of formula (XII) can beadministered orally, parenterally (IV, IM, depo-IM, SQ and depo-SQ),sublingually, intranasally (inhalation), intrathecally, topically andrectally. The invention here is the novel hydroxyethylene compounds offormula (XII). Dosage forms known to those skilled in the art aresuitable for delivery of the novel hydroxyethylene compounds of formula(XII).

[2385] Hydroxyethylene compounds of formula (XII) may be administeredenterally or parenterally. When administered orally, hydroxyethylenecompounds of formula (XII) can be administered in usual dosage forms fororal administration as is well known to those skilled in the art. Thesedosage forms include the usual solid unit dosage forms of tablets andcapsules as well as liquid dosage forms such as solutions, suspensionsand elixirs. When the solid dosage forms are used, it is preferred thatthey be of the sustained release type so that the hydroxyethylenecompounds of formula (XII) need to be administered only once or twicedaily.

[2386] The oral dosage forms are administered to the patient 1, 2, 3, or4 times daily. It is preferred that the hydroxyethylene compounds offormula (XII) be administered either three or fewer times, morepreferably once or twice daily. Hence, it is preferred that thehydroxyethylene compounds of formula (XII) be administered in oraldosage form. It is preferred that whatever oral dosage form is used,that it be designed so as to protect the hydroxyethylene compounds offormula (XII) from the acidic environment of the stomach. Enteric coatedtablets are well known to those skilled in the art. In addition,capsules filled with small spheres each coated to protect from theacidic stomach, are also well known to those skilled in the art. Whenadministered orally the therapeutically effective amount is from about0.1 mg/day to about 1,000 mg/day. It is preferred that the oral dosageis from about 1 mg/day to about 100 mg/day. It is more preferred thatthe oral dosage is from about 5 mg/day to about 50 mg/day. It isunderstood that while a patient may be started on one dose, that dosemay have to be varied over time as the patient's condition changes.

[2387] Hydroxyethylene compounds of formula (XII) may also beadvantageously delivered in a nano crystal dispersion formulation.Preparation of such formulations is described in U.S. Pat. No.5,145,684. And nano crystalline dispersions of, for example, HIVprotease inhibitors and their method of use are described in U.S. Pat.No. 6,045,829. The nano crystalline formulations typically affordgreater bioavailability of drug compounds.

[2388] In addition, the hydroxyethylene compounds of formula (XII) canbe administered parenterally. When admninistered parenterally they canbe administered IV, IM, depo-IM, SC or depo-SC. When administeredparenterally, the hydroxyethylene compounds of formula (XII) shoulddeliver a therapeutically effective amount about 0.5 to about 100mg/day, preferably from about 5 to about 50 mg daily. When a depoformulation is used for injection once a month or once every two weeks,the dose should be about 0.5 mg/day to about 50 mg/day or on a monthlyamount the dose for one month should be from about 15 mg to about 1,500mg. Because of the forgetfulness of the patients with Alzheimer'sdisease, it is preferred that the parenteral dosage form be a depo-IMinjection.

[2389] The hydroxyethylene compounds of formula (XII) can be givensublingually. When given sublingually, the hydroxyethylene compounds offormula (XII) should be given one thru four times daily in the sameamount as for IM administration.

[2390] The hydroxyethylene compounds of formula (XII) can be givenintranasally. When given by this route of administration, theappropriate dosage forms are a nasal spray or dry powder as is known tothose skilled in the art. The dosage of the hydroxyethylene compounds offormula (XII) for intranasal administration is the same as for IMadministration.

[2391] The hydroxyethylene compounds of formula (XII) can be givenintrathecally. When given by this route of administration theappropriate dosage form can be a parenteral dosage form as is known tothose skilled in the art. The dosage of the hydroxyethylene compounds offormula (XII) for intrathecal administration is the same as for IMadministration.

[2392] The hydroxyethylene compounds of formula (XII) can be giventopically. When given by this route of administration, the appropriatedosage form is a cream, ointment or patch. Because of the amount of thehydroxyethylene compounds of formula (XII) needed to administered thepatch is preferred. Further, two or more patches may be needed. Whenadministered topically, the dosage is from about 0.5 mg/day to about 200mg/day. However, the amount that can be delivered by a patch is limited.Therefore, two or more patches may be required. The number and size ofthe patch is not important, what is important is that a therapeuticallyeffective amount of the hydroxyethylene compounds of formula (XII) bedelivered as is known to those skilled in the art. The hydroxyethylenecompounds of formula (XII) can be administered rectally by suppositoryas is known to those skilled in the art. When administered bysuppository, the therapeutically effective amount is from about 0.5 mgto about 500 mg.

[2393] The hydroxyethylene compounds of formula (XII) can beadministered by implants as is known to those skilled in the art. Whenadministering a hydroxyethylene compound of formula (XII) by implant,the therapeutically effective amount is the same as for depotadministration.

[2394] Again, the invention here is a new method of usinghydroxyethylene compounds of formula (XII) and hydroxyethylene compoundsof formula (XII). Given a particular hydroxyethylene compound of formula(XII), and a desired dosage form, one skilled in the art would know howto prepare the appropriate dosage form for the hydroxyethylene compoundsof formula (XII).

[2395] The hydroxyethylene compounds of formula (XII) are used in thesame manner by the same routes of administration using the samepharmaceutical dosage forms and at the same dosing schedule for treatingpatients with MCI (mild cognitive impairment) and preventing or delayingthe onset of Alzheimer's disease in those who would progress from MCI toAD, for treating Down's syndrome, for treating humans who haveHereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, fortreating cerebral amyloid angiopathy and preventing its potentialconsequences, i.e. single and recurrent lobar hemorrhages, for treatingother degenerative dementias, including dementias of mixed vascular anddegenerative origin, dementia associated with Parkinson's disease,dementia associated with progressive supranuclear palsy, dementiaassociated with cortical basal degeneration, diffuse Lewy body type ofAlzheimer's disease. The hydroxyethylene compounds of formula (XII) canbe used with each other or with other agents used to treat or preventthe conditions listed above. Such agents include gamma-secretaseinhibitors, anti-amyloid vaccines and pharmaceutical agents such asdonepezil hydrochloride (ARICEPT™ Tablets), tacrine hydrochloride(COGNEX™ Capsules) or other acetylcholine esterase inhibitors and withdirect or indirect neurotropic agents of the future.

[2396] It should be apparent to one skilled in the art that the exactdosage and frequency of administration will depend on the particularhydroxyethylene compounds of formula (XII) administered, the particularcondition being treated, the severity of the condition being treated,the age, weight, general physical condition of the particular patient,and other medication the individual may be taking as is well known toadministering physicians who are skilled in this art.

DEFINITIONS AND CONVENTIONS

[2397] The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

I. CONVENTIONS FOR FORMULAS AND DEFINITIONS OF VARIABLES

[2398] The chemical formulas representing various compounds or molecularfragments in the specification and claims may contain variablesubstituents in addition to expressly defined structural features. Thesevariable substituents are identified by a letter or a letter followed bya numerical subscript, for example, “Z₁” or “R_(i)” where “i” is aninteger. These variable substituents are either monovalent or bivalent,that is, they represent a group attached to the formula by one or twochemical bonds. For example, a group Z₁ would represent a bivalentvariable if attached to the formula CH₃—C(═Z₁)H. Groups R_(i) and R_(j)would represent monovalent variable substituents if attached to theformula CH₃—CH₂—C(R_(i))(R_(j))H₂. When chemical formulas are drawn in alinear fashion, such as those above, variable substituents contained inparentheses are bonded to the atom immediately to the left of thevariable substituent enclosed in parenthesis. When two or moreconsecutive variable substituents are enclosed in parentheses, each ofthe consecutive variable substituents is bonded to the immediatelypreceding atom to the left which is not enclosed in parentheses. Thus,in the formula above, both R_(i) and R_(j) are bonded to the precedingcarbon atom. Also, for any molecule with an established system of carbonatom numbering, such as steroids, these carbon atoms are designated asC_(i), where “i” is the integer corresponding to the carbon atom number.For example, C₆ represents the 6 position or carbon atom number in thesteroid nucleus as traditionally designated by those skilled in the artof steroid chemistry. Likewise the term “R₆” represents a variablesubstituent (either monovalent or bivalent) at the C₆ position.

[2399] Chemical formulas or portions thereof drawn in a linear fashionrepresent atoms in a linear chain. The symbol “—” in general representsa bond between two atoms in the chain. Thus CH₃—O—CH₂—CH(R₁)—CH₃represents a 2-substituted-i-methoxypropane compound. In a similarfashion, the symbol “═” represents a double bond, e.g.,CH₂═C(R_(i))—O—CH₃, and the symbol “≡” represents a triple bond, e.g.,HC≡C—CH(R_(i))—CH₂—CH₃. Carbonyl groups are represented in either one oftwo ways: —CO— or —C(═O)—, with the former being preferred forsimplicity.

[2400] A rigid cyclic (ring) structure for any compounds herein definesan orientation with respect to the plane of the ring for substituentsattached to each carbon atom of the rigid cyclic compound. For saturatedcompounds which have two substituents attached to a carbon atom which ispart of a cyclic system, —C(X₁)(X₂)— the two substituents may be ineither an axial or equatorial position relative to the ring and maychange between axial/equatorial. However, the position of the twosubstituents relative to the ring and each other remains fixed. Whileeither substituent at times may lie in the plane of the ring(equatorial) rather than above or below the plane (axial), onesubstituent is always above the other. In chemical structural formulasdepicting such compounds, a substituent (X₁) which is “below” anothersubstituent (X₂) will be identified as being in the alpha (α)configuration and is identified by a broken, dashed or dotted lineattachment to the carbon atom, i.e., by the symbol “- - -” or “. . .”.The corresponding substituent attached “above” (X₂) the other (X₁) isidentified as being in the beta (β) configuration and is indicated by anunbroken line attachment to the carbon atom.

[2401] When a variable substituent is bivalent, the valences may betaken together or separately or both in the definition of the variable.For example, a variable R_(i) attached to a carbon atom as —C(═R,)—might be bivalent and be defined as oxo or keto (thus forming a carbonylgroup (—CO—) or as two separately attached monovalent variablesubstituents α—R_(1−j) and β—R_(i−k. When a bivalent variable, R) _(i),is defined to consist of two monovalent variable substituents, theconvention used to define the bivalent variable is of the form“α—R_(1−j):β—R_(1−k)” or some variant thereof. In such a case bothα—R_(i−j) and β—R_(i−k) are attached to the carbon atom to give—C(α—R_(i−j))(β—R_(i−k)—. For example, when the bivalent variable R) ₆,—C(═R₆)— is defined to consist of two monovalent variable substituents,the two monovalent variable substituents are α—R⁶⁻¹:β—R⁶⁻², . . . .α—R⁶⁻⁹:β—R⁶⁻¹⁰, etc, giving —C(α—R⁶⁻¹) (β—R⁶⁻²)—, . . . .—C(α—R⁶⁻⁹)(β—R⁶⁻¹⁰)—, etc. Likewise, for the bivalent variable R₁₁,—C(═R₁₁)—, two monovalent variable substituents are α—R₁₁:β—R¹¹⁻². For aring substituent for which separate a and 1 orientations do not exist(e.g. due to the presence of a carbon carbon double bond in the ring),and for a substituent bonded to a carbon atom which is not part of aring the above convention is still used, but the α and β designationsare omitted.

[2402] Just as a bivalent variable may be defined as two separatemonovalent variable substituents, two separate monovalent variablesubstituents may be defined to be taken together to form a bivalentvariable. For example, in the formula —C₁(R_(i))H—C₂(R_(j))H— (C₁ and C₂define arbitrarily a first and second carbon atom, respectively) R_(i)and R_(j) may be defined to be taken together to form (1) a second bondbetween C₁ and C₂ or (2) a bivalent group such as oxa (—O—) and theformula thereby describes an epoxide. When R_(i) and R_(j) are takentogether to form a more complex entity, such as the group —X—Y—, thenthe orientation of the entity is such that C, in the above formula isbonded to X and C₂ is bonded to Y. Thus, by convention the designation“. . . R_(i) and R_(j) are taken together to form —CH₂—CH₂—O—CO—. . .”means a lactone in which the carbonyl is bonded to C₂. However, whendesignated “. . . R_(j) and R₁ are taken together to form —CO—0—CH₂—CH₂—the convention means a lactone in which the carbonyl is bonded to C₁.

[2403] The carbon atom content of variable substituents is indicated inone of two ways. The first method uses a prefix to the entire name ofthe variable such as “C₁-C₄”, where both “1 ” and “4” are integersrepresenting the minimum and maximum number of carbon atoms in thevariable. The prefix is separated from the variable by a space. Forexample, “C₁-C₄ alkyl” represents alkyl of 1 through 4 carbon atoms,(including isomeric forms thereof unless an express indication to thecontrary is given). Whenever this single prefix is given, the prefixindicates the entire carbon atom content of the variable being defined.Thus C₂-C₄ alkoxycarbonyl describes a group CH₃—(CH₂)_(n)—O—CO— where nis zero, one or two. By the second method the carbon atom content ofonly each portion of the definition is indicated separately by enclosingthe “C_(i)-C_(j)” designation in parentheses and placing it immediately(no intervening space) before the portion of the definition beingdefined. By this optional convention (C₁-C₃)alkoxycarbonyl has the samemeaning as C₂-C₄ alkoxycarbonyl because the “C₁-C₃” refers only to thecarbon atom content of the alkoxy group. Similarly while both C₂-C₆alkoxyalkyl and (C₁-C₃)alkoxy(C₁-C₃)alkyl define alkoxyalkyl groupscontaining from 2 to 6 carbon atoms, the two definitions differ sincethe former definition allows either the alkoxy or alkyl portion alone tocontain 4 or 5 carbon atoms while the latter definition limits either ofthese groups to 3 carbon atoms.

[2404] When the claims contain a fairly complex (cyclic) substituent, atthe end of the phrase naming/designating that particular substituentwill be a notation in (parentheses) which will correspond to the samename/designation in one of the CHARTS which will also set forth thechemical structural formula of that particular substituent.

[2405] It is to be understood that the recitation of numerical ranges byendpoints includes all numbers and fractions subsumed within that range(e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

[2406] It is to be understood that all numbers and fractions thereof arepresumed to be modified by the term “about.”

[2407] It is to be understood that “a” as used herein includes both thesingular and plural.

[2408] The general definitions used herein have the following meaningswithin the scope of the present invention.

II. DEFINITIONS

[2409] All temperatures are in degrees Celsius.

[2410] TLC refers to thin-layer chromatography.

[2411] psi refers to pounds/in².

[2412] HPLC refers to high pressure liquid chromatography.

[2413] THF refers to tetrahydrofuran.

[2414] DMF refers to dimethylformamide.

[2415] EDC refers to ethyl-1-(3-dimethylaminopropyl)carbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[2416] NBS refers to N-bromosuccinimide.

[2417] TEA refers to triethylamine.

[2418] BOC refers to 1,1-dimethylethoxy carbonyl or t-butoxycarbonyl,—CO—O—C(CH₃)₃.

[2419] CBZ refers to benzyloxycarbonyl, —CO—O—CH₂-φ.

[2420] TFA refers to trifluoracetic acid, CF₃—COOH.

[2421] CDI refers to 1,1 ′-carbonyldiimidazole.

[2422] Saline refers to an aqueous saturated sodium chloride solution.

[2423] Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

[2424] CMR refers to C-13 magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from TMS.

[2425] NMR refers to nuclear (proton) magnetic resonance spectroscopy,chemical shifts are reported in ppm (d) downfield from TMS.

[2426] -φ refers to phenyl (C₆H₅).

[2427] MS refers to mass spectrometry expressed as m/e, m/z ormass/charge unit. MH⁺ refers to the positive ion of a parent plus ahydrogen atom. El refers to electron impact. CI refers to chemicalionization. FAB refers to fast atom bombardment.

[2428] HRMS refers to high resolution mass spectrometry.

[2429] Ether refers to diethyl ether.

[2430] Pharmaceutically acceptable refers to those properties and/orsubstances which are acceptable to the patient from apharmacological/toxicological point of view and to the manufacturingpharmaceutical chemist from a physical/chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

[2431] When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

[2432] When the solubility of a solid in a solvent is used the ratio ofthe solid to the solvent is weight/volume (wt/v).

[2433] BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate.

[2434] TBDMSC1 refers to t-butyldimethylsilyl chloride.

[2435] TBDMSOTf refers to t-butyldimethylsilyl trifluosulfonic acidester.

[2436] Trisomy 21 refers to Down's Syndrome.

[2437] Ac=acetyl (methylearbonyl)

[2438] aq.=aqueous

[2439] bd=broad doublet

[2440] bs=broad singlet

[2441] c=concentration (g/mL)

[2442] cc=cubic centimeter

[2443] d=doublet

[2444] DCM=dichloromethane=methylene chloride=CH₂Cl₂

[2445] de=diastereomeric excess

[2446] EDTA=ethylene diamine tetraacetic acid

[2447] eq.=equivalents

[2448] EtOAc=ethyl acetate

[2449] EtOH=ethanol

[2450] g=grams

[2451] HOBT=1-hydroxybenzotriazole

[2452] h=hour

[2453] IC₅₀=inhibitory concentration of a compound that reduces enzymeactivity by half.

[2454] iso=an alkyl chain having the ending group 2-methylpropyl, i.e.—CH(CH₃)₂.

[2455] IM=intramuscularly

[2456] IV=intravenously

[2457] SC=subcutaneously

[2458] L=liter

[2459] LDA=lithium diisopropyl amide

[2460] m=multiplet

[2461] max=maximum

[2462] mg=milligram

[2463] mL=milliliter

[2464] mm=millimeter

[2465] mM=millimolar

[2466] mmol=millimole

[2467] mp=melting point

[2468] MeOH=methanol

[2469] meq=milliequivalent

[2470] MsOH=methanesulfonic acid

[2471] n=normal, i.e. unbranched, e.g. n-Pr is —CH₂—CH₂—CH₃

[2472] N=normal

[2473] ng=nanogram

[2474] m=nanometers

[2475] OD=optical density

[2476] PEPC=1-(3-(1-pyrrolidinyl)propyl)-3-ethylcarbodiimide

[2477] pg=picogram

[2478] pM=picoMolar

[2479] Rf=ratio of movement of a substance on a thin layer chromatogramin comparison to the movement of the solvent front.

[2480] δ=units of measurement in nuclear magnetic resonance spectroscopywhich are relative to a standard, e.g. tetramethyl silane.

[2481] q=quartet

[2482] quint.=quintet

[2483] rpm=rotations per minute

[2484] s=singlet

[2485] t=triplet

[2486] t or tert=tertiary in an alkyl chain, e.g. t-butyl is —C(CH₃)₃.

[2487] μL=microliter

[2488] μM=micromolar (an expression of concentration inmicromoles/liter)

[2489] s=singlet

[2490] t=triplet

[2491] UV=ultraviolet

[2492] Unless otherwise indicated, all functional group radicals (e.g.,alkyl, aryl, cycloalkyl, cyclic heteroaryl, heterocycle, etc.) can besubstituted or unsubstituted. Substituted functional group radicals canbe substituted with one or more substituents, unless indicatedotherwise. Suitable substituents for substituted functional groupradicals generally include halogen, hydroxy, alkoxy, alkyl, aryl,arylalkyl, alkylaryl, arylalkoxy, and the like. It will be understoodthat the terminology “X radical substituted by a/an Y” includes the “X”radical being substituted by two or more “Y”, unless indicatedotherwise.

[2493] “Alkyl” refers to linear or branched, saturated aliphatichydrocarbon radicals, such as, for example, methyl, ethyl, propyl,butyl, octyl, isopropyl, tert-butyl, sec-pentyl, and the like.

[2494] “Cycloalkyl” refers to cyclic aliphatic hydrocarbon radicals,such as, for example, 3- to 8-member hydrocarbon rings (e.g., cyclohexylor cyclopentyl), bicyclic 4- to 10-member hydrocarbon ring systems, anda tricyclic 8- to 14-member hydrocarbon ring systems. Monocycliccycloalkyl groups include, for example, cyclohexane and cyclopentane.Multicyclic cycloalkyl groups include cyclohexyl, cyclopentyl, and 1, 2,3, 4-tetrahydrohaphthyl for example.

[2495] “Heterocycle” refers to cyclic, non-aromatic radicals containingat least two carbon atoms and 1 to 3 heteroatoms selected from O, N, andS as members of at least one ring. Examples of such radicals include 3-to 8-member rings; bicyclic 4- to 10-member ring systems, and tricyclic8- to 14-member ring systems, where at least one ring (and in someinstances each of the rings) of any of these examples contains 1 to 3heteroatoms selected from 0, N, and S as members of the ring. Monocyclicheterocyclic groups include morpholinyl, piperazinyl, andtetrahydrofuranyl, for example. Multicyclic heterocyclic groups includedecahydroquinoline, cyclohexene oxide, and 3-amino-3-azabicyclo [3.3.0]octane, for example.

[2496] “Alkylene” refers to bivalent, linear or branched, saturatedaliphatic hydrocarbon radicals, such as, for example, methylene,ethylene, propylene, butylene, octylene, isopropylene, tert-butylene,sec-pentylene, and the like.

[2497] “Alkenyl” refers to linear or branched aliphatic hydrocarbonradicals containing at least one double bond, such as, for example,ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-methyl-1-propenyl, and thelike.

[2498] “Alkynyl” refers to linear or branched aliphatic hydrocarbonradicals containing at least one triple bond, such as, for example,ethynyl (acetyl), 1-propynyl, 2-propynyl, 1- butynyl, and the like.

[2499] “Aryl” refers to cyclic aromatic hydrocarbon radicals having asingle ring, such as phenyl, multiple rings, such as biphenyl, andmultiple condensed rings, such as naphthyl and anthryl. Monocyclic arylgroups include phenyl, for example. Multicyclic aryl groups includenaphthyl and anthryl, for example.

[2500] “Amine” includes primary, secondary and tertiary amines which maybe in straight or branched chains or, in the case of secondary andtertiary amines within rings (e.g. morpholine and piperazine).

[2501] “Heteroaryl” refers to a cyclic aromatic rings having 1 to 4hetero atoms selected from S, O, and N; and aromatic 7 to 10 memberedorganic stable bicyclic rings having 1 to 5 hetero atoms selected fromS, O, and N. Examples of such radicals include 3- to 8-member rings;bicyclic 4- to 10-member ring systems; and tricyclic 8- to 14-memberring systems, where at least one ring (and in some instances each of therings) of any of these examples contains 1 to 3 heteroatoms selectedfrom O, N, and S as members of the ring.

[2502] “Acyloxy” refers to the groups R—C(O)O—, substituted R—C(O)O—,cycloalkyl-C(O)O—, aryl—C(O)O—, and heterocyclic—C(O)O where R =alkyl,and alkyl, cycloalkyl, aryl, and heterocyclic are as defined herein.

[2503] “Acylamino” refers to the groups R—C(O)N—, substituted R—C(O)N—,cycloalkyl-C(O)N—, aryl—C(O)N—, and heterocyclic—C(O)N—where R=alkyl,and alkyl, cycloalkyl, aryl, and heterocyclic are as defined herein.

[2504] “Amide” and “amido” refer to a functional group containing acarbon atom double-bonded to an oxygen atom and additionally singlybonded to a nitrogen atom [—C(O)—N]. “Primary” amide describes anunsubstituted amide group [—C(O)—NH₂]. “Secondary” and “tertiary” amidesare amides in which nitrogen is substituted with one and twonon-hydrogen groups respectively. The term “lactam” refers to a cyclizedamide, i.e. a secondary or tertiary amide wherein the carbonyl carbonand the nitrogen atom are adjacent members of a ring.

[2505] “Halogen” refers to fluoro, chloro, bromo, and iodo radicals.

[2506] “Lactone” refers to cyclized ester of a carboxylic acid.

[2507] “Thio” refers to the replacement of oxygen by sulfur in a definedradical. Examples of thio compound include alkylthioxy compounds (e.g.alkyl—S—).

[2508] “Thioxyalkyl” refers to the divalent radical —S—alkyl-, wherealkyl is as defined above. Examples of thioxyalkyl moietites includealkyl-S-alkyl moieties, such as CH₃—S—CH₂CH₂—.

[2509] “Alkoxy” refers to the radical —O—-alkyl with alkyl as definedabove. Alkoxy groups include, for example, methoxy, ethoxy, propoxy,isopropoxy, and the like.

[2510] “Arylalkyl” and “aralkyl” refer to an alkyl radical substitutedwith an aryl.

[2511] “Alkylaryl” refers to an aryl radical substituted with an alkyl.

[2512] All the terms “carboxyl”, “carboxylic acid”, “carboxylate” and“carbamoyl” are terms referring to functional groups containing a carbonatom double-bonded to an oxygen atom [C═O, also called an acyl or acarbonyl group, represented in linear notation as —C(O)—] andadditionally single- bonded to another oxygen atom [—C(O)—O—], and inthe case of carbamoyl, additionally a nitrogen atom is also bonded tothe carbonyl carbon to give —N—C(O)—O—. Carboxyl, carboxylate andcarbamate include the corresponding pharmaceutically acceptable C₁-C₆alkyl and C₆-C₁₀ aryl esters and secondary and tertiary amides.

[2513] Combinations of these terms for functional group radicals arealso used. Typically, the last term in the designation contains theradical that bonds to the remainder of the chemical structure. Forexample, “haloalkyl” refers to an alkyl radical substituted by ahalogen, “cycloalkylalkyl” refers to alkyl radical substituted by acycloalkyl, and “alkylcycloalkyl” refers to a cycloalkyl radicalsubstituted by an alkyl.

EXAMPLES

[2514] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, practice the presentinvention to its fullest extent. The following detailed examplesdescribe how to prepare the various compounds and/or perform the variousprocesses of the invention and are to be construed as merelyillustrative, and not limitations of the preceding disclosure in any waywhatsoever. Those skilled in the art will promptly recognize appropriatevariations from the procedures both as to reactants and as to reactionconditions and techniques.

[2515] Preparations of the novel compounds of the present inventionutilizing the hydroxyethylene isostere are illustrated in the followingexamples, which are not, however, intended to be any limitation thereof.

[2516] Methods of Synthesis

[2517] The following reaction schemes illustrate methods of constructionof the hydroxyethylene dipeptide isosteres provided in examples 1-13.Variations of starting materials may be used in these reactions toprepare hydroxyethylene cores having other side chain groups.Substitutions of available starting materials to achieve the desiredside chain variants will be apparent to one of ordinary skill in theart.

[2518] Alternatively hydroxyethylenes may be prepared by the methoddescribed below. Synthesis of the Boc-3,5-difluorophenylalanine threoepoxide starting material was adapted from the procedure of Luly, J R,et al. J. Org. Chem. 1987, 52, 1487-1492 for the synthesis ofBoc-phenylalanine threo epoxide (Scheme II). The starting materialutilized in the preparation of Boc-3,5-difluorophenylalanine threoepoxide was Boc protected 1-3,5-difluorophenylalanine available fromSynthetech, Inc. (1290 Industrial Way, P. O. Box 646, Albany, Oreg.97321 USA).

[2519] The chiral amine synthesis, the initial alkylation step andfurther manipulation to the lactone were accomplished based onliterature procedures as follows: Dragovich, P S, et al. J. Med. Chem.1999, 42, 1203-1222; Askin, D., et al. J. Org. Chem. 1992, 57,2771-2773. Cleavage of the Boc protecting group and subsequent couplingof the acid was accomplished using the procedures for deprotection ofthe amine and EDC coupling given below. Ring-opening of the lactone tothe final product was accomplished using a AlMe₃-mediated coupling stepaccording to the literature procedure of S. F. Martin et al.,Tetrahedron Lett. 1998, 39,1517-1520.

[2520] Removal of a Boc-Protecting Group From a Protected Amine toGenerate Free Amine:

[2521] For example, the Boc-protected alpha-amino lactone intermediateof either Scheme I or II was dissolved in a trifluoroaceticacid/dichloromethane (1/1) solution. The reaction was monitored by TLCto confirm the consumption of starting material at which time thesolvents were removed under reduced pressure to yield the free amine,which was used without further purification.

[2522] Coupling Deprotected Amine with a Selected N-Terminal CappingGroup:

[2523] For example, 2-(N,N-dipropyl) amidobenzoic acid (1.0 equiv.) wasdissolved in 30 mL of dry dichloromethane, then HOBT (2.0 equiv.),functionalized α-amino lactone from the step above (1.0 equiv.) and TEA(5 equiv.) were added and all was stirred for 20 minutes. EDC (1.2equiv.) was added and the mixture was stirred overnight under anatmosphere of nitrogen. The reaction was then diluted with water andextracted with EtOAc (3×). The organic layers were washed with aqueouscitric acid (2×), sat. NaHCO3 (2×), brine, then dried over MgSO₄, andthe solvent was removed under vacuum. The product of this step may thenbe subjected to a lactone ring aminolysis to provide the desired amidebond. TABLE 1 Enzyme inhibition assay results for structures having thepeptide backbone: (XII)

Example R_(N) R_(C) Examples 1-6: R2 = —CH(CH₃)₂ and R1 = —CH₂CH(CH₃)₂ 1

 2

 3

 4

 5

 6

*Assay procedure described in the Example 70 Examples 7-10: R2 = —CH₂CH₃and R1 = —CH₂-3,5-difluorophenyl  7

 8

 9

10

Example 11: R2 = benzyl and R1 = —CH₂-3,5-difluorophenyl 11

Examples 12: R2 = propyl and R1 = —CH₂-3,5-difluorophenyl 12

Examples 13: R1 = methyl and R2 = —CH₂-3,5-difluorophenyl 13

Example 1

[2524] This compound was prepared employing the amino and hydroxyprotected hydroxyethylene prepared via Scheme I. The compound wasprepared standard resin supported peptide synthetic methods usingstandard HOBt, EDC coupling procedures described under Scheme II.Boc-Phe was esterified to the resin support. The Boc protecting groupwas removed from the Phe by treatment with trifluoroacetic acid indicloromethane (TFA/DCM) and then coupled with Boc-Glu (mono ester) asdescribed above. The cycle of amino deprotection and HOBt/EDC couplingwas repeated with Boc-Ala, then with the protected hydroxyethylenemoiety of Scheme I and then Boc-Met and finally Ac-Val. The glutamylester was removed via LiOH hydrolysis. The silyl group was removed fromthe hydroxyl function by treatment with tetra-t-butylammonium fluoride[(t-Bu)₄NF] in THF. Molecular Formula C₄₁H₆₈N₆O₉S Molecular Weight821.10 Mass spec (MH+) 821

Example 2

[2525] p-Aminomethylbenzoic acid methyl ester (commercially available)was coupled with the hydroxyethylene moiety of Scheme I using standardEDC/HOBt coupling. The Boc protecting group was removed from theN-terminal and then subsequently coupled with Boc-Val-Met. The methylester was hydroylzed as described above and silyl group was removed fromthe hydroxyl function by treatment with tetra-t-butylammonium fluoride[(t-Bu)₄NF] in THF. Molecular Formula C₃₅H₅₈N₄O₈S Molecular Weight694.927 tlc Rf (solvent) Rf = 0.28 in 5% Methanol/dichloromethanePurification: 5% Methanol/dichloromethane Mass spec (MH+) 695

Example 3

[2526] The hydroxyethylene moiety of Scheme I was coupled with thedimethyl ester of 3,5-dicarboxycyclohexylamine as prepared in Scheme VIA. This intermediate was in turn deprotected at the N-terminal withTFA/DCM and then coupled with the alpha-hydroxy-naphthylacetic acid. Themethyl esters were hydrolyzed with LiOH and then the silyl group wasremoved from the hydroxyl function by treatment withtetra-t-butylammonium fluoride [(t-Bu)₄NF] in THF. Molecular Weight584.7 tlc Rf (solvent) 0.15 (10% MeOH/CH2C12) Purification: Flashchromatography Mass spec (M+H+) (CI) 584.7

Example 4

[2527] The protected hydroxyethylene as produced in Scheme I was coupledwith the the dimethyl ester of 3,5-dicarboxycyclohexylamine (Scheme VIA). The diester was hydrolyzed with LiOH and the silyl protecting groupremoved by treatment with tetra-t- butylammonium fluoride [(t-Bu)₄NF] inTHF. Molecular Formula C₂₅ H₄₄ N₂ O₈ Molecular Weight 500.6 tlc Rf(solvent) 0.15 (5% MeOH/CH₂Cl₂) Purification: Acid/base extraction Massspec (M−H+) (CI) 498.7

Example 5 (Diastereomeric at the α-Hydroxy-Naphthylacetyl)

[2528] The hydroxyethylene moiety of Scheme I was coupled with themethyl 3-(1-aminopropyl)-4-benzoate (commercially available). Thisintermediate was in turn deprotected at the N-terminus with TFA/DCM(1:1) and then coupled with the alpha-hydroxy-naphthylacetic acid. Themethyl ester was hydrolyzed with LiOH and then the silyl group wasremoved from the hydroxyl function by treatment withtetra-t-butylammonium fluoride [(t-Bu)₄NF] in THF. Molecular FormulaC₃₄H₄₄N₂O₆ Molecular Weight 576.73 tlc Rf (solvent) Rf = 0.12 in 10%Methanol/dichloromethane Purification: 10% Methanol/dichloromethane Massspec (MH+) 577

Example 6

[2529] This pentapeptide isostere was prepared to test the efficacy ofthe α-hydroxy-naphthylacetic acid as an N-terminal group peptidomimeticin an oligopeptide sequence that demonstrated good activity (see Ex. 1).The hydroxyethylene moiety was prepared via the method of Scheme I.Resin supported synthesis was employed to prepare the molecule bybonding Boc-Phg to a resin support and then sequentially constructed byremoval of the Boc protecting group and HOBt/EDC coupling in turn withglutamic acid methyl ester, valine, the hydroxyethylene isostere ofScheme I and finally with U.- hydroxy-naphthylacetic acid. The productwas then cleaved from the solid support and protecting groups wereremoved as described in the examples above. Molecular FormulaC₄₁H₅₄N₄O₁₀ Molecular Weight 762.9 Purification: 500 analytical HPLCtrace (Gradient: 20-50% [B] in 30 minutes, [A] Buffer 0.1% TFA/H2O; [B]Buffer = 0.1% TFA/Acetonitrile) revealed two diastereomers eluting at19.4 and 21.0 minutes Mass spec (M+Na+) 763.6 (785.6) [801.6] [M+K+]

[2530] The preparation of examples 1-6, as described in Table 1 above,is outlined in Scheme I.

Example 7

[2531] After the C-terminal coupling was accomplished as describedabove, the lactone was subjected to aminolysis at refluxing temperatureswith 3,5-dimethylcyclohexylamine in the presence of AlMe₃ and a suitableorganic solvent to provide the subject compound. Molecular Formula C36H51 F2 N3 O6 Molecular Weight 659 tlc Rf (solvent) 0.15 (5% iPrOH/CHCl3)Purification: Flash chromatography Mass spec (M+H+) (CI) 660.4

Example 8

[2532] After the C-terminal coupling was accomplished as describedabove, the lactone was subjected to aminolysis at refluxing temperatureswith 6-aminohexanoic acid in the presence of AlMe₃ and a suitableorganic solvent to provide the subject compound. Molecular Formula C₃₄H₄₇ F₂ N₃ O₆ Molecular Weight 631 tlc Rf (solvent) 0.15 (5% MeOH/CH2Cl2)Purification: Flash chromatography Mass spec (M+H+) (CI) 632.2

Example 9

[2533] After the C-terminal coupling was accomplished as describedabove, the lactone was subjected to aminolysis at refluxing temperatureswith 8-aminooctanoic acid in the presence of AlMe₃ and a suitableorganic solvent which was then dissolved in MeOH and treated with HClgas to provide the desired methyl ester. Molecular Formula C₃₇ H₅₃ F₂ N₃O₆ Molecular Weight 673 tlc Rf (solvent) 0.4 (5% iPrOH/CHCl₃)Purification: Flash chromatography Mass spec (M+H+) (CI) 674.4

Example 10

[2534] After the C-terminal coupling was accomplished as describedabove, the lactone was subjected to aminolysis at refluxing temperatureswith 4-carboxycyclohexylmethylamine in the presence of AlMe₃ and asuitable organic solvent to provide the subject compound. MolecularFormula C₃₆ H₄₉ F₂ N₃ O6 Molecular Weight 657 tlc Rf (solvent) 0.3 (10%MeOH/CH₂Cl₂) Purification: Flash chromatography Mass spec (M+H+) (CI)658.4

Example 11

[2535] The subject compound was prepared as in Example 10 except that inthe first step of preparation of the chiral oxazolidine intermediate,3-phenylpropionyl chloride (Aldrich Chemical) was substituted forn-butanoyl chloride. Molecular Formula C₄₁H₅₁F₂N₃O₆ Molecular Weight719.86 Mass spec (M + Na +) 743

Example 12

[2536] The subject compound was prepared as in Example 10 except that inthe first step of preparation of the chiral oxazolidine intermediate,n-pentanoyl chloride was substituted for n-butanoyl chloride. MolecularFormula C₃₇H₅₁F₂N₃O₆ Molecular Weight 671.37 Mass spec (M + Na + )694.37

Example 13

[2537] The subject compound was prepared as in Example 10 except that inthe first step of preparation of the chiral oxazolidine intermediate,n-propionyl chloride was substituted for n-butanoyl chloride. MolecularFormula C₃₅H₄₇F₂N₃O₆ Molecular Weight 643.34 Mass spec (M + Na +) 666.34

[2538] The compound formulae referred to in Examples 14-22 correspond tothose recited in CHART A. Furthermore, the following examples relate tothose compounds recited in CHART A where R₁=—(CH₂)3,5-difluorobenzyl,R₂=Et, R_(N)=N′,N′-dipropylisophthalamide,R_(c)=anti-4-aminomethylcyclohexanecarboxylic acid, and PROTECTING GROUPis Boc. The identity of the R₂ substituent is determined by the startingmaterial (i.e. compounds of formula (XIII)) used in the synthesis of theintermediate (VII) as is outlined in CHART B. The intermediate (VII),prepared according to CHART B, is then incorporated into the syntheticscheme for the preparation of hydroxyethylene compounds of formula(XII), as outlined in CHART A, by reaction with the epoxide (VI).

Example 14(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carbamicacid tert-butyl ester (III)

[2539] (L)-2-tert-Butoxycarbonylamino-3-(3,5-difluorophenyl)-propionicacid (Synthetech Inc., II, 2.66 g, 8.83 mmol) was dissolved in a mixtureof dry THF (5 mL) and dry DMF (2 mL) at rt. 1,1-Carbonyldiimidazole(1.71 g, 10.6 mmol) was added in one portion to this solution. After gasevolution ceased, a solution of N-methyl-O-methylhydroxylaminehydrochloride (0.955 g, 9.79 mmol) and diisopropylethylamine (1.6 mL,9.19 mmol) in DMF (4 mL) was added at rt by syringe. This was stirred atrt for 17 h, whereupon the reaction was quenched with 10% citric acid.The mixture was extracted with EtOAc. The organic extract was washed(saturated NaHCO₃, saturated NaCl), dried (MgSO₄), filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography (30% EtOAc/hexanes elution) to give an oil as product:M+Na+367.1.

Example 15 (L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acidtert-butyl ester (IV)

[2540](L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carbamicacid tert-butyl ester (III, 2.56 g) was dissolved in dry THF (50 mL) andcooled to 0 ° C. To this mixture was added powder lithium aluminumhydride (285 mg) in portions over 5 min. The resulting suspension wasstirred at 0° C. for 1 h. Reaction was quenched at 0° C. by slowaddition of saturated citric acid until gas evolution ceased, followedby dropwise addition of 10% aqueous citric acid (30 mL). This was thenallowed to warm to rt. The layers were separated and the aqueousextracted with Et₂O. The combined organic extracts were washed(saturated NaHCO₃, saturated NaCi), dried (MgSO₄), filtered, andconcentrated under reduced pressure to give a solid, which was usedwithout further purification.

Example 16 (L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid tert-butylester(V)

[2541] Potassium hydride (35% suspension in mineral oil, 1.76 g) wassuspended in a mixture of dry THF (20 mL) and DMSO (4 mL), and wascooled to 0° C. 1,1,1,3,3,3-Hexamethyldisilazane (4.0 mL) was added bysyringe, and the mixture was stirred for 45 min at 0° C.Methyltriphenylphosphonium bromide (5.57 g) was added, and the resultingyellow slurry was stirred at 0° C. for 1 h, whereupon the mixture wascooled to −78° C. A solution of (L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acid tert-butyl ester (IV, 2.2 g)in THF (15 mL) at −78° C. was added by cannula. The resulting suspensionwas stirred at −78° C. for 15 min, then was allowed to warm to rt for 16h. MeOH (2 mL) and half-saturated sodium bicarbonate solution (100 mL)were added, and the mixture was extracted with EtOAc (2×50 mL). Thecombined organic extracts were washed (water, saturated NaCl) dried(MgSO₄), filtered, and concentrated under reduced pressure. The residuewas purified by flash chromatography (10-20% Et₂O/hexanes) to give asolid as product: M+Na+306.1.

Example 17 (1S, 2R)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamicacid tert-butyl ester (VI)

[2542] (L)-[1 -(3,5-Difluorobenzyl)allyl]-carbamic acid tert-butylester(V, 3.3 g) was dissolved in CH₂Cl₂ (130 mL) and m-chloroperbenzoicacid (50-55% pure, 16.0 g) was added with stirring at rt. After 23 h,the reaction mixture was diluted with Et₂O, washed (10% Na₂SO₃,saturated NaHCO₃, saturated NaCl), dried (MgSO₄), filtered, andconcentrated under reduced pressure to give a solid: M+Na+322.1.

Example 18 (1S,2S, 4R)-[1-(3,5-Difluorobenzyl)-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamicacid tert-butyl ester (VIII)

[2543] (1S, 2S)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acidtert-butyl ester (VI, 113 mg) and 1-((3aS,8aR)-2,2-Dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-3-yl)-butan-1-one(VII, 94 mg) were combined in dry THF (3 mL), and cooled to −78° C. Tothis solution was added BuLi (2.5 M in hexanes, 0.32 nim) over 5 min.,whereupon the solution was allowed to warm to 0° C. for 1.5 h. Thereaction mixture was partitioned between 0.5 N HCl (4 mL) and 1:1EtOAc/hexanes (2×4 mL). The combined organic layers were dried (MgSO₄),filtered, and concentrated under reduced pressure. The residue waspurified by flash chromatography (20-30% EtOAc/hexanes) to give an oil:MH+559.1.

Example 19[2-(3,5-Difluorophenyl)-1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2-(S)-yl)-ethyl]-carbamicacid tert-butyl ester (IX)

[2544] (1S,2S, 4R)-[1 -(3,5-Difluorobenzyl)-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-djoxazole-3-carbonyl)-2-hydroxyhexyl]-carbamicacid tert-butyl ester (VIII, 60 mg) was dissolved in 5:1 toluene/CH₂Cl₂(3 mL), and p-toluenesulfonic acid monohydrate (23 mg) was added. Thiswas stirred at rt for 18 h. The mixture was then filtered, andpartitioned between half-saturated NaHCO₃ (3 mL) and 1:1 EtOAc/hexanes(2×3 mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated under reduced pressure. Flash chromatography of the residueafforded desired product as a solid: MH+370.2.

Example 205S-[1S-Amino-2-(3,5-difluorophenyl)ethyl]-3R-ethyldihydrofuran-2-one (X)

[2545][2-(3,5-Difluorophenyl)-1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2-(S)-yl)-ethyl]-carbamicacid tert-butyl ester (IX, 313 mg) was dissolved in CH₂Cl₂ (1 ML) at rt,whereupon CF₃COOH (1 mL) was added. This was stirred at rt for 1 h, thenconcentrated under reduced pressure. This was used in the next reactionwithout further purification.

Example 21 N-{2-(3,5-Difluorophenyl)-(1S, 2S,4R)-[1-(4-ethyl-5-oxotetrahydrofuran-2-yl)]ethyl}-N′,N′-dipropylisophthalamide(XI)

[2546] 5S-[1S-Amino-2-(3,5-difluorophenyl)ethyl]-3R-ethyldihydrofuran-2-one (X, 228mg theoretical) was combined with triethylamine (0.7 mL) in dry DMF (2mL) at 0° C. N,N-Dipropylisophthalamic acid (242 mg) was added anddissolved. 1-Hydroxybenzotriazole (224 mg) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (320 mg)were added in succession. The mixture was stirred at 0° C. for 5 min.,then allowed to warm to rt for 4 h. This was then diluted with 10%citric acid, and extracted 3× with EtOAc. The combined organic extractswere washed (saturated NaHCO₃, saturated NaCl), dried (MgSO₄), filtered,and concentrated under reduced pressure. The residue was purified byflash chromatography (40% EtOAc/hexanes elution) to give a solid:MH+501.3.

Example 224-(anti)-{[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-methyl}cyclohexanecarboxylicacid (XII)

[2547] Anti-4-Aminomethylcyclohexanecarboxylic acid (57 mg) wassuspended in 1,2-dichloroethane (2 mL), and cooled to 0° C.Trimethylaluminum (2.0 M in toluene, 0.21 niL) was added, followed by asolution of N-{2-(3,5-Difluorophenyl)-(lS, 2S,4R)-[1-(4-ethyl-5-oxotetrahydrofuran-2-yl)]ethyl}-N′,N′-dipropylisophthalamide(XI, 30 mg) in 1,2-dichloroethane (1 mL). This was then warmed to refluxfor 1.5 h, whereupon the reaction mixture was cooled to 0° C., and thereaction quenched with 3 N HCl (2 mL). The slurry was stirred at 0° C.for 30 min, and then extracted with 3×5 mL 10% iPrOH/CHCl₃. The combinedorganic extracts were dried (MgSO₄), filtered, and concentrated underreduced pressure. The residue was purified by flash chromatography(5-10% MeOH/CH₂Cl₂ elution) to give a solid: MH+658.4.

[2548] The compound formulae referred to in Examples 23-24 correspond tothose recited in CHART B. Furthermore, the following examples relate tothose compounds recited in CHART B R₂ Et.

Example 23 N-(1S, 2R)-(2-Hydroxyindan-1-yl)-butyramide (XV)

[2549] (1S, 2R)-cis-1-Amino-2-indanol (XIV, 1.5 g) was dissolved withtriethylamine (1.5 mL) in dry THF (45 mL), and cooled to 0° C. Butyrylchloride (XIII, 1.05 mL) was added by syringe, and the resultantsolution stirred 0° C. for 20 min, whereupon the reaction mixture waspartitioned between half-saturated NH₄Cl (45 mL) and EtOAc (2×45 mL).The combined organic layers were dried dried (MgSO₄), filtered, andconcentrated under reduced pressure to give a solid, which was taken tothe next reaction without further purification.

Example 24 1-((3aS,8aR)-2,2-Dimethyl-8,8a-dihydro-3aH-indenoli,2-d]oxazol-3-yl)-butan-1-one(VII)

[2550] N-(1S, 2R)-(2-Hydroxyindan-1-yl)-butyramide (XV, 2.2 g) and2-methoxypropene (5 mL) were combined with CH₂Cl₂ (70 mL) at rt, andmethanesulfonic acid (0.05 mL) was added. After 20 min at rt, thereaction mixture was partitioned between half-saturated NaHCO₃ (30 mL)and CH₂Cl₂ (2∴30 mL). The combined organic layers were dried dried(MgSO₄), filtered, and concentrated under reduced pressure to give anoil as product: MH+260.1.

[2551] Examples 25-30 recited below relate to the synthesis forN-terminus capping groups.

Example 25 Hydroxylated and Benzylated N-terminal Capping Groups

[2552] The making of hydroxylated and benzylated N-terminal cappinggroups from aromatic acetic acid starting materials is illustrated inScheme III below. Moersch, G W and Zwiesler, M L. (Synthesis, 1971,647-648, ref. 1 in Scheme III) demonstrate a synthesis useful forpreparing an arylalkylhydroxycarboxylic acid N-terminus capping group.The procedure here provides alpha hydroxylation of 1-naphthylaceticacid, using lithium diethylamine and oxygen. Hon, Yung-Son, Chang,Rong-Chi, Chau, Tay-Yuan (Heterocycles, 1990, Vol. 31, No. 10,1745-1750, ref. 2 in Scheme III) demonstrate a synthesis of thecorresponding benzyl ether from the α-hydroxyaromatic by esterificationof the carboxy function and etherification with benzyl bromide. Eitherthe α-hydroxy acid or the benzyl ether derivative is suitable as aN-terminal cap.

Example 26 Preparation of Carboxybenzamides

[2553]

[2554] Methyl isophthalate (Aldrich Chemical, Milwaukee, Wis., (1 equiv,11.1 mmol) was dissolved in 50:50 THF : DMF (20 mL) before the additionof 1,1′carbonylduimidazole (CDI) (1.2 equiv, 13.3 mmol) at ambienttemperature. Upon addition of CDI, an evolution of gas (CO₂), wasobserved. After gas evolution subsided (approximately one minute orless), the amine (1.2 equiv, 13.3 mmol) was added. After 12 h ofstirring at ambient temperature, the reaction was partitioned betweensaturated aqueous NH₄Cl and ethyl acetate, and the aqueous layer wasextracted twice more with ethyl acetate. The organic extracts were thenwashed with saturated aqueous solutions of NauCO₃ and NaCl, and driedover anhydrous MgSO₄ or NaSO₄. Filtration of the drying agent andremoval of solvents in vacuo gave the crude white solid or clear oil.Purification of these compounds if needed was achieved viachromatography on silica gel with 3040% ethyl acetate in hexanes.

[2555] The methyl isophthalate mono-alkyl or di-alkyl amide was thentreated with LiOH.H₂O (3 equiv, 33.3 inmol) in a minimum amount of 1:2:1THF:MeOH:H₂O and allowed to stir overnight at ambient temperature. After12 h, the solvents were removed in vacuo and subsequently partitionedbetween H₂O and ethyl acetate. If emulsions prohibit separation of thetwo layers, a small amount of brine was added to aid in separation. Theaqueous layer was extracted once more with ethyl acetate (to remove anyunreacted starting material). The aqueous layer was then acidified withconcentrated HCl until pH≦3. The cloudy-white acidic aqueous solutionthus obtained was then extracted three times with ethyl acetate. Thesecombined organic extracts were dried over anhydrous MgSO₄ or NaSO₄.Filtration of the drying agent and removal of solvents in vacuo gave asolid. The mono- or di-alkyl amide isophthalate was used crude in thenext reaction.

Example 27 Preparation of Carboxybenzamides

[2556]

[2557] Methyl isophthalate (1 equiv, 11.1 mmol) was dissolved in 50:50THF: DMF (20 mL) before the addition of 1,1′carbonyldiimidazole (CDI)(1.2 equiv, 13.3 mmol) at ambient temperature. Upon addition of CDI,evolution of gas (CO₂), was observed. After gas evolution subsided(approximately one minute or less), the amine (1.2 equiv, 13.3 mmol)dissolved in DMF and diisopropylethyl amine (1.2 equiv, 13.3 mmol) wasadded. After 12 h of stirring at ambient temperature, the reaction waspartitioned between saturated aqueous NH₄Cl and ethyl acetate, and theaqueous layer was extracted twice more with ethyl acetate. The organicextracts were then washed with saturated aqueous solutions of NaHCO₃ andNaCl, and dried over anhydrous MgSO₄ or NaSO₄. Filtration of the dryingagent and removal of solvents in vacuo gave a solid or oil. Purificationof these compounds if needed was achieved via chromatography on silicagel with 30-40% ethyl acetate in hexanes.

[2558] The methyl isophthalate mono-alkyl or di-alkyl amide (1 equiv,11.1 mmol) was then treated with LiOH.H₂O (3 equiv, 33.3 mmol) in aminimum amount of 1:2:1 THF:MeOH:H₂O and allowed to stir overnight atambient temperature. After 12 h, the solvents were removed in vacuo andsubsequently partitioned between H₂O and ethyl acetate. If emulsionsprohibit separation of the two layers, a small amount of brine was addedto aid in separation. The aqueous layer was extracted once more withethyl acetate (to remove any unreacted starting material). The aqueouslayer was then acidified with concentrated HCl until pH≦3. Thecloudy-white acidic aqueous solution thus obtained was then extractedthree times with ethyl acetate. These combined organic extracts weredried over anhydrous MgSO₄ or Na₂SO₄. Filtration of the drying agent andremoval of solvents in vacuo gave a solid. The mono- or di-alkyl amideisophthalate was used crude in the next reaction.

Example 28 Preparation of Primary Amide

[2559]

[2560] Methyl isophthalate (1 equiv, 11.1 mmol) was dissolved in 50:50THF:DMF (20 mL) before the addition of 1,1′carbonyldiimidazole (CDI)(1.2 equiv, 13.3 mmol) at ambient temperature. Upon addition of CDI, anevolution of gas (CO₂), was observed. After five minutes, ammonia gaswas bubbled into the solution through a syringe needle for 1 h. Sincethe reaction was heating up due to an exotherm, the reaction was cooledto 0° C. for the duration of the hour. The reaction was then leftstirring under a balloon of ammonia overnight at ambient temperature.After 12 h, the reaction was partitioned between saturated aqueous NH₄Cland ethyl acetate, and the aqueous layer was extracted twice more withethyl acetate. The organic extracts were then washed with saturatedaqueous solutions of NaHCO₃ and NaCl, and dried over anhydrous MgSO₄ orNaSO₄. Filtration of the drying agent and removal of solvents in vacuogave a solid or oil. Purification via chromatography on silica gel with5% isopropanol in chloroform gave the desired primary amide.

[2561] The methyl isophthalate primary amide (7.26 mmol) was thentreated with LiOH.H₂O (3 equiv, 21.8 mmol) in a minimum amount of 1:2:1THF:MeOH:H₂O and allowed to stir overnight at ambient temperature. After12 h, the solvents were removed in vacuo and subsequently partitionedbetween H₂O and ethyl acetate. The aqueous layer was extracted once morewith ethyl acetate (to remove any unreacted starting material). Theaqueous layer was then acidified with concentrated HCl until pH≦3. Thecloudy-white acidic aqueous solution thus obtained was then extractedthree times with ethyl acetate. These combined organic extracts weredried over anhydrous MgSO₄ or NaSO₄. Filtration of the drying agent andremoval of solvents in vacuo gave a solid. The mono-or di-alkyl amideisophthalate was used crude in the next reaction.

Example 29 Preparation of Heterocyclic Amides

[2562]

Scheme IVD

[2563] Methyl isophthalate (1.2 equiv, 2.78 mmol) was dissolved in dryCH2Cl2 and three drops of DMF (catalytic). The solution was cooled to 0°C. before the drop-wise addition of oxalyl chloride (2 equiv, 4.63mmol). The mixture was stirred at 0° C. for 1 h. The mixture neverdissolved. After 1 h, the solvents were removed in vacuo. The acidchloride was left under vacuum overnight.

[2564] The crude acid chloride (1 equiv, 2.78 mmol) was dissolved in dryCH₂Cl₂ and cooled to 0° C. before the addition of NEt₃ (5 equiv, 11.6mmol) and N-methyl piperidine (6 equiv, 13.9 mmol). The reaction wasstirred at 0° C. for 2 h before the solvents were removed in vacuo. Theresidue was diluted with H₂O and ethyl acetate and the layers wereseparated. The aqueous layer was extracted twice more with ethylacetate, and the combined organic extracts were washed with saturatedaqueous NaHCO₃, and dried over anhydrous MgSO₄. Filtration of the dryingagent and removal of solvents in vacuo gave the crude product.

[2565] The crude amide (1 equiv, 2.19 mmol) was then treated withLiOH.H₂O (1 equiv, 2.19 mmol) in a minimum amount of 1:2:1 THF:MeOH:H₂Oand allowed to stir overnight at ambient temperature. After 12 h, thesolvents were removed in vacuo and subsequently partitioned between H₂Oand ethyl acetate. The aqueous layer was extracted once more with ethylacetate (to remove any unreacted starting material.) Removal of H₂O fromaqueous layer in vacuo gave a solid.

Example 30 Preparation of aromatic α-hydroxy acids (illustrated by thepreparation with α-hydroxy-α-(2-biphenyl)acetic acid)

[2566]

[2567] A solution of CH₂Cl₂ (25 mL) and oxalyl chloride (2 niL, 21.16mmol) was placed in a 100-mL round bottom flask kept under nitrogen. Theoxalyl chloride solution was stirred at −50 to 60° C. Me₂SO (2.5 mL,35.82 mmol) was dissolved in CH₂Cl₂ (5mL). The Me₂SO was added dropwiseto the stirred oxalyl chloride solution at −50 to −60° C. The reactionmixture was stirred for 2 min and the 2-phenylbenzyl alcohol (16.28 mmolin 10 mL CH₂Cl₂) was added within 5 min; stirring was continued for anadditional 60 min. TEA (11.30 mL, 81.4 mmol) was added and the reactionmixture was stirred for 60 min and then allowed to warm to roomtemperature. Water (60 mL) was then added and the aqueous layer wasreextracted with additional CH₂Cl₂ (60 mL). The organic layers werecombined, washed with saturated NaCl solution (120 mL), and dried overanhydrous MgSO₄. The filtered solution was concentrated in a rotaryevaporator to dryness. The oil was chromatographed on silica gel (98: 2hexanes: EtOAc) to give 1.

[2568] A mixture of 5.46 mmol of aromatic aldehyde(1) in 10 mL of CHCl₃and β-cyclodextrins (CDs) ( 0.11 mmol) and triethylbenzylammoniumchloride(TEBA)( 0.273 mmol)in a flask equipped with a magnetic stirrerand dropping funnel was stirred for 20 minute at 50° C. Then 10 g ofsodium hydroxide dissolved in 10 mL of water was added dropwise to theflask with stirring. After completion of this addition, the reaction wascontinued for 8 h with the temperature maintained at 50° C. Then enoughof distilled water was added to dissolve the precipitate formed duringthe reaction, and the resulting solution was thoroughly washed withether, adjusted to pH 3 with dilute hydrochloric acid and extracted with3×30 mL of ether. The extract was dried with anhydrous sodium sulfate,then evaporated to dryness and the remaining precipitate was subjectedto column chromatography on silica gel using DCM:MeOH:AcOH (95:5:1) togive 2.

[2569] Examples 31 and 32 recited below relate to the synthesis forN-terminus capping groups.

Example 31 1-Amino-3,5-cis,cis-dimethyl Cyclohexyldicarboxylate

[2570] To 10 g (47.85mmole) of dimethyl-5-isophthalate in 25 ml ofacetic acid and 50 ml of methanol was added 5 g of 5% rhodium in aluminain a high-pressure bottle, which was saturated with hydrogen at 55 psiand shaken for one week of time.

[2571] The mixture was then filtered through a thick layer of Celitecake and rinse with methanol three times, the solvents was concentratedand the crude solid was triturated with diethyl ether and filteredagain, it afforded 1-amino-3,5-cis,cis-dimethyl cyclohexyldicarboxylate,reverse phase HPLC has shown a purity of 94.4%.

Example 32 1-Amino-3,5-cis,cis-dimethoxy Cyclohexane

[2572] To 10 g (65.36mmole) of 3,5-dimethoxyaniline was reacted asdescribed in the procedure above and afforded 1-amino-3,5-cis,cis-dimethoxy cyclohexane.

[2573] Following the general procedure as outlined in Examples 14-22 andmaking non-critical variations the following substitute amines offormula (XII) are obtained. These substitute amines of formula (XII) arelisted in Tables 2, 3, and 4 as Examples. TABLE 2

Example MH+ C-terminus (X) N-[(1S,2S,4R)-1-(3,5-Difluorobenzyl)-4-(syn,syn)-(3,5-dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide 33 660.4

6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2- 34632 NH(CH₂)₅CO₂H (R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoic acid5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2- 35618.3 NH(CH₂)₄CO₂H (R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoic acid4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2- 36603.7 NH(CH₂)₃CO₂H (R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyric acid3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2- 37590.3 NH(CH₂)₂CO₂H (R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionic acid8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2- 38660.4 NH(CH₂)₇CO₂H (R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoic acid8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-39 674.4 NH(CH₂)₇CO₂ (R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoicacid methyl ester MeN-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy- 40574.3 NHBu hexyl]-N,N-dipropyl-isophthalamideN-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl- 41574.5 NHiBu hexyl]-N,N-dipropyl-isophthalamideN-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy- 42608.3 NHBn hexyl]-N,N-dipropyl-isophthalamideN-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide 43 614.3

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide 44 586.3

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide 45 589.3

N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide 46 588.1

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide 47 576.3

4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)- cyclohexanecarboxylicacid methyl ester 48 672.0

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide 49608.0

[2574] TABLE 3

Example MH+ X4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-50 658.4 Et(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-51 644.3 Me(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-52 672.3 nPr(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-53 686.3 iBu(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-54 630.3 H (S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-55 720.3 Bnbenzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid

[2575] TABLE 4

Example MH+ X Y4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethy-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid 56 672.2

Et 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylic acid methyl ester 57 686

Et N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide 58 631.2

Me N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl- isophthalamide 59 574.3

Me N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl isophthalamide 60617.3

Me N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide 61 602.3

Me N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl- isophthalamide 62652.3

Me N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl- isophthalamide 63588.3

Me N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)- 64 608.3NHBn Me hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamideN-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro- 65 626.3 NH-(4-F)—Bn Mebenzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide

[2576] TABLE 5

Example MH+ XN-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide 66 622.3

N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide 67 598.3

N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide 68 556.3

Example 69 Benzyl(1S)-2-(3,5-difluorophenyl)-1-[(2R)-oxiranyl]ethylcarbamate (VI)

[2577] Following the general procedure of EXAMPLE 17 and making noncritical variations but starting with the alcohol (IV) Benzyl (1S,2R)-3-chloro-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate, the titlecompound is obtained.

[2578] While this invention has been described with respect to variousspecific examples and embodiments, it is to be understood that theinvention is not limited thereby and should only be construed byinterpretation of the scope of the appended claims.

We claim:
 1. A hydroxyethylene compound of the formula

where R₁ is: (I) C₁-C₆ alkyl, unsubstituted or substituted with one, twoor three C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —NH_(2,) —C≡N, —CF₃, or—N₃, (II) —(CH₂)₁ ₂—S—CH₃, (III) —CH₂—CH₂—S—CH₃, (IV) —CH₂—(C₂-C₆alkenyl) unsubstituted or substituted by one —F, (V)—(CH₂)₀₋₃—(R_(1-aryl)) where R_(1-aryl) is phenyl, 1-naphthyl,2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstitutedor substituted on the aryl ring with one or two of the followingsubstituents which can be the same or different: (A) C₁-C₃ alkyl, (B)—CF₃, (C) —F, Cl, —Br and —I, (D) C₁-C₃ alkoxy, (E) —O—CF₃, (F) —NH₂,(G) —OH, or (H) —C—N, (VI) —(CH₂)_(n1)-(R_(1-heteroaryl)) where n, is 0,1, 2, or 3 and R_(1-heteroaryl) is: (A) pyridinyl, (B) pyrimidinyl, (C)quinolinyl, (D) indenyl, (E) indanyl, (F) benzothiophenyl, (G) indolyl,(H) indolinyl, (I) pyridazinyl, (J) pyrazinyl, (K) isoindolyl, (L)isoquinolyl, (M) quinazolinyl, (N) quinoxalinyl, (O) phthalazinyl, (P)imidazolyl, (Q) isoxazolyl, (R) pyrazolyl, (S) oxazolyl, (T) thiazolyl,(U) indolizinyl, (V) indazolyl, (W) benzothiazolyl, (X) benzimidazolyl,(Y) benzofiranyl, (Z) furanyl, (AA) thienyl, (BB) pyrrolyl, (CC)oxadiazolyl, (DD) thiadiazolyl, (EE) triazolyl, (FF) tetrazolyl, (GG)1,4-benzodioxan (HH) purinyl, (II) oxazolopyridinyl, (JJ)imidazopyridinyl, (KK) isothiazolyl, (LL) naphthyridinyl, (MM)cinnolinyl, (NN) carbazolyl, (OO) P-carbolinyl, (PP) isochromanyl, (QQ)chromanyl, (RR) flirazanyl, (SS) tetrahydroisoquinoline, (TT)isoindolinyl, (UU) isobenzotetrahydrofuranyl, (VV)isobenzotetrahydrothienyl, (WW) isobenzothiophenyl, (XX) benzoxazolyl,or (YY) pyridopyridinyl, where the R_(1-heteroayl) group is bonded to—(CH₂)₀₋₃- by any ring atom of the parent R_(N-heteroaryl) groupsubstituted by hydrogen such that the new bond to the R_(1-heteroaryl)group replaces the hydrogen atom and its bond, where heteroaryl isunsubstituted or substituted with one or two: (1) C₁-C₃ alkyl, (2) —CF₃,(3) —F, Cl, —Br, or —I, (4) C₁-C₃ alkoxy, (5) —O—CF₃, (6) —NH₂, (7) —OH,or (8) —CN, with the proviso that when n₁ is zero R_(1-heteroaryl) isnot bonded to the carbon chain by nitrogen, or (VII)—(CH₂)_(n1)-(R_(1-heterocycle)) where n₁ is as defined above andR_(1-heterocycle) is: (A) morpholinyl, (B) thiomorpholinyl, (C)thiomorpholinyl S-oxide, (D) thiomorpholinyl S,S-dioxide, (E)piperazinyl, (F) homopiperazinyl, (G) pyrrolidinyl, (H) pyrrolinyl, (I)tetrahydropyranyl, (J) piperidinyl, (K) tetrahydrofuranyl, or (L)tetrahydrothiophenyl, where the R_(1-heterocycle) group is bonded by anyatom of the parent R_(1-heterocycle) group substituted by hydrogen suchthat the new bond to the R_(1-heteroaryl) group replaces the hydrogenatom and its bond, where heterocycle is unsubstituted or substitutedwith one or two: (1)═O, (2) C₁-C₃ alkyl, (3) —CF₃, (4) —F, Cl, —Br and—I, (5) C₁-C₃ alkoxy, (6) —O—CF₃, (7) —NH₂, (8) —OH, or (9) —C≡N, withthe proviso that when n₁ is zero R_(1-heterocycle) is not bonded to thecarbon chain by nitrogen; where R₂ is: (I) —H, (II) C₁-C₆ alkyl, or(III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is (C₃-C₆)cycloalkyl, R_(1-aryl) orR_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as definedabove, where R_(N) is: (I) R_(N-1)-X_(N)- where XN is: (A) —CO—, (B)—SO₂—, (C) —(CR′RW″)₁₋₆ where R′ and R″ are the same or different andare —H or C₁-C₄ alkyl, (D) —CO—(CR′R″)₁₋₆-X_(N-1) where X_(N-1) is —O—,—S— and —NR′R″- and where R′ and R″ are as defined above, (E) a singlebond; where R_(N-1) is: (A) RNary, where R_(N-aryl) is phenyl,1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two,three or four of the following substituents which can be the same ordifferent and are: (1) C₁-C₆ alkyl, (2) —F, —Cl, —Br, or —I, (3)—OH, (4)—NO₂, (5) —CO—OH, (6) —C≡N, (7) —CO—NR_(N-2) R_(N-3)where R_(N-2) andR_(N-3) are the same or different and are: (a) —H, (b) —C₁-C₆ alkylunsubstituted or substituted with one (i) —OH, or (ii) —NH₂, (c) —C₁-C₆alkyl unsubstituted or substituted with one to three —F, —Cl, —Br, or—I, (d) —C₃-C₇ cycloalkyl, (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), (f)—(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl), (g) —C₁-C₆ alkenyl with one or twodouble bonds, (h) —C₁-C₆ alkynyl with one or two triple bonds, (i)—C₁-C₆ alkyl chain with one double bond and one triple bond, (j)—R_(1-aryl) where R_(1-aryl) is as defined above, or (k)—R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (8)—CO—(C₃-C₁₂ alkyl), (9) —CO—(C₃-C₆ cycloalkyl), (10)—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (11)—CO—R_(1-heterocycle) where R_(1-heterocycle) is as defined above, (12)—CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl or pyrrolidinyl where each group is unsubstituted orsubstituted with one or two C₁-C₃ alkyl, (13) —CO—O—R_(N-5) whereR_(N-5) is: (a) C₁-C₆ alkyl, or (b) —(CH₂)₀₋₂-(R_(1-aryl)) whereR_(1-aryl) is as defined above, (14) —SO₂—NR_(N-2)R_(N-3)where R_(N-2)and R_(N-3) are as defined above, (15) —SO—(C₁-C₈ alkyl), (16)—SO₂(C₃-C₁₂ alkyl), (17) —NH—CO—O—R_(N-5) where R_(N-5) is as definedabove, (18) —NH—CO—N(C₁-C₃ alkyl)₂, (19) —N—CS—N(C₁-C₃ alkyl)₂, (20)—N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as defined above, (21)—NR_(N-2) R_(N-3) where R_(N-2) and R_(N-3) can be the same or differentand are as defined above, (22) —R_(N-4) where R_(N-4) is as definedabove, (23) —O—CO—(C₁-C₆ alkyl), (24) —O—CO—N(C₁-C₃ alkyl)₂, (25)—O—CS—N(C₁-C₃ alkyl)₂, (26) —O—(C₁-C₆ alkyl), (27) —O—(C₂-C₅alkyl)-COOH, (28) —S—(C₁-C₆ alkyl), (29) C₁-C₆ alkyl unsubstituted orsubstituted with 1, 2, 3, 4, or 5 —F, (30) —O—(C₁-C₆ alkyl unsubstitutedor substituted with 1, 2, 3, 4, or 5—F, or (31) —O-φ, (B)—R_(N-heteroaryl) where R_(N-heteroaryl) is: (A) pyridinyl, (B)pyrimidinyl, (C) quinolinyl, (D) indenyl, (E) indanyl, (F)benzothiophenyl, (G) indolyl, (H) indolinyl, (I) pyridazinyl, (J)pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M) quinazolinyl, (N)quinoxalinyl, (O) phthalazinyl, (P) imidazolyl, (Q) isoxazolyl, (R)pyrazolyl, (S) oxazolyl, (T) thiazolyl, (U) indolizinyl, (V) indazolyl,(W) benzothiazolyl, (X) benzimidazolyl, (Y) benzofiranyl, (Z) furanyl,(AA) thienyl, (BB) pyrrolyl, (CC) oxadiazolyl, (DD) thiadiazolyl, (EE)triazolyl, (FF) tetrazolyl, (GG) 1,4-benzodioxan (HH) purinyl, (II)oxazolopyridinyl, (JJ) imidazopyridinyl, (KK) isothiazolyl, (LL)naphthyridinyl, (MM) cinnolinyl, (NN) carbazolyl, (O) β-carbolinyl, (PP)isochromanyl, (QQ) chromanyl, (RR) furazanyl, (SS)tetrahydroisoquinoline, (TT) isoindolinyl, (UU)isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl, wherethe R_(N-heteroaryl) group is bonded by any atom of the parentR_(N-heteroaryl) group substituted by hydrogen such that the new bond tothe R_(N-heteroaryl) group replaces the hydrogen atom and its bond,where heteroaryl is unsubstituted or substituted with one or two: (1)C₁-C₆ alkyl, (2) —F, —Cl, —Br, or —I, (3) —OH, (4) —NO₂, (5)—CO—OH, (6)—CN, (7) —CO—NR_(N-2) R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are: (a) —H, (b) —C₁-C₆ alkyl unsubstituted or substitutedwith one (i) —OH, or (ii) —NH₂, (c) —C₁-C₆ alkyl unsubstituted orsubstituted with 1, 2, or 3 —F, —Cl, —Br, or —I, (d) —C₃-C₇ cycloalkyl,(e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), (f) —(C₁-C₆ alkyl)-O—(C₁-C₃alkyl), (g) —C₁-C₆ alkenyl with one or two double bonds, (h) —C₁-C₆alkynyl with one or two triple bonds, (i) —C₁-C₆ alkyl chain with onedouble bond and one triple bond, (j) —R_(1-aryl) where R_(1-aryl) is asdefined above, or (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is asdefined above, (8) —CO—(C₃-C₁₂ alkyl), (9) —CO—(C₃-C₆ cycloalkyl), (10)—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (11)—CO—R_(1-heterocycle) where R_(1-heterocycle is as defined above,) (12)—CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl or pyrrolidinyl where each group is unsubstituted orsubstituted with one or two C₁-C₃ alkyl, (13) —CO—O—R_(N-5) whereR_(N-5) is: (a) C₁-C₆ alkyl, or (b) —(CH₂)₀₋₂-(R_(1-aryl)) whereR_(1-aryl) is as defined above, (14) —SO₂—NR_(N-2) R_(N-3) where R_(N-2)and R_(N-3) are as defined above, (15) —SO—(C₁-C₈ alkyl), (16)—SO₂(C₃-C₁₂ alkyl), (17) —NH—CO—O—R_(N-5) where R_(N-5) is as definedabove, (18) —NH—CO—N(C₁-C₃ alkyl)₂, (19) —N—CS—N(C₁-C₃ alkyl)₂, (20)—N(C₁-C₃ alkyl)-CO—RN₅ where R_(N-5) is as defined above, (21)—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) can be the same or differentand are as defined above, (22) —R_(N-4) where R_(N-4) is as definedabove, (23) —O—CO—(C₁-C₆ alkyl), (24) —O—CO—N(C₁-C₃ alkyl)₂, (25)—O—CS—N(C₁-C₃ alkyl)₂, (26) —O—(C₁-C₆ alkyl), (27) —O—(C₂-C₅alkyl)-COOH, or (28) —S—(C₁-C₆ alkyl), (C) —R_(N-aryl)—R_(N-aryl) where—R_(N-aryl) is as defined above, (D) —R_(N-aryl)—R_(N-heteroaryl) where—R_(N-aryl) and —R_(N-heteroaryl) are as defined above, (E)—R_(n-heteroaryl)—R_(N-aryl) where —R_(N-aryl) and —R_(N-heteroaryl) areas defined above, (F) —R_(N-heteroaryl)—R_(N-heteroaryl) whereR_(N-heteroaryl) is as defined above, (G) —R_(N-aryl)-O—R_(R) _(N-aryl)where —R_(N-aryl) is as defined above, (H) —R_(N-aryl)—S-R_(N-aryl)where —R_(N-aryl) is as defined above, (I)—R_(N-heteroaryl)-O—R_(N-heteroaryl) where R_(N-heteroaryl) is asdefined above, (J) —R_(N-heteroaryl)—S—R_(N-heteroaryl) whereR_(N-heteroaryl) is as defined above, (K) —R_(N-aryl)—CO—R_(N-aryl)where —R_(N-aryl) is as defined above, (L)—R_(N-aryl)CO—R_(N-heteroaryl) where —R_(N-aryl) and R_(N-heteroaryl)are as defined above, (M) —R_(N-aryl)SO₂—R_(N-aryl) where —R_(N-aryl) isas defined above, (N) —R_(N-heteroaryl)—CO—R_(N-heteroaryl) whereR_(N-heteroaryl) is as defined above, (O)—R_(N-heteroaryl)—SO₂—R_(N-heteroaryl) where R_(N-heteroaryl) is asdefined above, (P) —R_(N-aryl)-O—(C₁-C₈ alkyl)-φ where R_(N-aryl) is asdefined above, (Q) —R_(N-aryl)—S—(C₁-C₈ alkyl)-φ where R_(N-aryl) is asdefined above, (R) —R_(N-heteroary)—O—(C₁-C₈ alkyl)-φ whereR_(N-heteroaryl) is as defined above, or (S) —R_(N-heteroaryl)—S—(C₁-C₈alkyl)-φ where R_(N-heteroaryl) is as defined above, (II) A—X_(N)- whereX_(N) is —CO—, wherein A is (A) —T-E—(Q)_(m′), (1) where —T is

where (a) x=1 when y=1 and x=2 when y=0, (b)m is 0, 1, 2 or 3, (c) thevalues of x and y vary independently on each carbon when m is 2 and 3,and (d) R′″ varies independently on each carbon and is H, (C₁-C₂) alkyl,phenyl, or phenyl(C₁-C₃)alkyl; (2) -E is (a) C₁-C₅ alkyl, but only if m′does not equal 0, (b) methylthioxy(C₂-C₄)alkyl, (c) an aryl group having5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (d) aheterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12atoms when fused, (e) a mono or fused ring cycloalkyl group having 5 to10 carbon atoms, (f) biphenyl, (g) diphenyl ether, (h) diphenylketone,(i) phenyl(C₁-C₈)alkyloxyphenyl, or (j) C₁-C₆ alkoxy; (3) —Q is (a)C₁-C₃ alkyl, (b) C₁-C₃ alkoxy, (C) C₁-C₃ alkylthioxy, (d) C₁-C₆alkylacylamino, (e) C₁-C₆ alkylacyloxy, (f) amido (including primary,C₁-C₆ alkyl and phenyl secondary and tertiary amino moieties), (g) C₁-C₆alkylamino (h) phenylamino, (i) carbamyl (including C₁-C₆ alkyl andphenyl amides and esters), (j) carboxyl (including C₁-C₆ alkyl andphenyl esters), (k) carboxy(C₂-C₅)alkoxy, (l) carboxy(C₂-C₅)alkylthioxy,(m) heterocyclylacyl, (n) heteroarylacyl, or (o) hydroxyl; (4)m′ is 0,1, 2 or 3; (B) -E(Q)_(m″) wherein E and —Q are as defined as above andm″ is 0, 1, 2, or 3; (C) —T-E wherein -E and —Q are as defined as above;or (D) -E wherein -E is as defined as above; (III) —CO—(C₁-C₆ alkyl)where alkyl is unsubstituted or substituted with one or two: (A) —OH,(B) —C₁-C₆ alkoxy, (C) —C₁-C₆ thioalkoxy, (D) —CO—O—R_(N-8) whereR_(N-8) is —H, C₁-C₆ alkyl or (E) —CO—NR_(N-2) R_(N-3)where R_(N-2) andR_(N-3) are the same or different and are as defined above, (F)—CO—R_(N-4) where R_(N-4) is as defined above, (G) —SO₂—(C₁-C₈ alkyl),(H) —SO2—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above, (I) —NH—CO—(C₁-C₆ alkyl), (J)—NH—CO—O—R_(N-8) where R_(N-8) is as defined above, (K)—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same or different andare as defined above, (L) —R_(N-4) where R_(N-4) is as defined above,(M) —O—CO—(C₁-C₆ alkyl), (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) isthe same or different and are as defined above, or (O) —O—(C₁-C₅alkyl)-COOH, (IV) —CO—(C₁-C₃ alkyl)-O—(C₁-C₃ alkyl) where alkyl isunsubstituted or substituted with one or two (A) —OH, (B) —C₁-C₆ alkoxy,(C) —C₁-C₆ thioalkoxy, (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C6alkyl or (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the sameor different and are as defined above, (F) —CO—R_(N-4) where R_(N-4) isas defined above, (G) —SO₂—(C₁-C₈ alkyl), (H) —SO2—NR_(N-2)R_(N-3)whereR_(N-2) and R_(N-3) are the same or different and are as defined above,(I) —NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8) where R_(N-8) is asdefined above, (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are thesame or different and are as defined above, (L) —R_(N-4) where R_(N-4)is as defined above, (M) —O—CO—(C₁-C₆ alkyl), (N) —O—CO—NRN8R_(N-8)where the R_(N-8) are the same or different and are as defined above, or(O) —O—(C₁-C₅ alkyl)-COOH, (V) —CO—(C₁-C₃ alkyl)-S—(C₁-C₃ alkyl) wherealkyl is unsubstituted or substituted with one or two (A) —OH, (B)—C₁-C₆ alkoxy, (C) —C₁-C₆ thioalkoxy, (D) —CO—O—RN₈ where R_(N-8) is —H,C₁-C₆ alkyl or -φ, (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) arethe same or different and are as defined above, (F) —CO—R_(N-4) whereR_(N-4) is as defined above, (G) —SO₂—(C₁-C₈ alkyl), (H)—SO₂—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) are the same or differentand are as defined above, (I) —NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8)where R_(N-8) is as defined above, (K) —NR_(N-2)R_(N-3)where R_(N-2) andR_(N-3) are the same or different and are as defined above, (L) —R_(N-4)where R_(N-4) is as defined above, (M) —O—CO—(C₁-C₆ alkyl), (N)—O—CO—NR_(N-8)R_(N-8) where the R_(N-8) are the same or different andare as defined above, or (O) —O—(C₁-C₅ alkyl)-COOH, (VI)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl) )where R_(N-aryl) and R_(N-heteroaryl), are as defined above, whereR_(N-10) is: (A) —H, (B) C₁-C₆ alkyl, (C) C₃-C₇ cycloalkyl, (D) C₂-C₆alkenyl with one double bond, (E) C₂-C₆ alkynyl with one triple bond,(F) R_(1-aryl) where R_(1-aryl) is as defined above, or (G)R_(N-heteroaryl) where R_(N-heteroaryl) is as defined above; where B is—O—, —NH—, or —N(C₁-C₆ alkyl)-; where R_(c) is: (I) —(C₁-C₁₀)alkyl-K₁₋₃in which: (A) the alkyl chain is unsubstituted or substituted with one—OH, (B) the alkyl chain is unsubstituted or substituted with one C₁-C₆alkoxy unsubstituted or substituted with 1-5 —F, (C) the alkyl chain isunsubstituted or substituted with one —O-φ, (D) the alkyl chain isunsubstituted or substituted with 1-5 —F, (E) the alkyl chain isunsubstituted or substituted with a combination of up to three atoms ofoxygen and sulfur each such atom replacing one carbon, (F) each K is:(1) H, (2) C₁-C₃ alkyl, (3) C₁-C₃ alkoxy, (4) C₁-C₃ alkylthioxy, (5)C₁-C₆ alkylacylamino, (6) C₁-C₆ alkylacyloxy, (7) amido (8) C₁-C₆alkylamino (9) phenylamino, (10) carbamyl (11) carboxyl (12)carboxy(C₂-C₅)alkoxy, (13) carboxy(C₂-C₅)alkylthioxy, (14)heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted orsubstituted with C₁-C₆ alkyl, (17) hydroxyl, or (18) carboxyl methylester; (II)-(CH₂)₀₋₃-J-[(—(CH₂)₀₋₃-K]₁₋₃ where K is as defined above andJ is: (A) a 5 to 7 atom monocyclic aryl group, (B) a 8 to 12 atommulticyclic aryl group, (C) a 5 to 7 atom heterocyclic group, (D) a 8 to12 atom multicyclic heterocyclic group, or (E) a 5 to 10 atom monocyclicor multicyclic cycloalkyl group; (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkylwhere cycloalkyl can be unsubstituted or substituted with one, two orthree (A) C₁-C₃ alkyl unsubstituted or substituted with 1, 2, 3, or 4—F, —Cl, —Br, or —I, (B) —CO—OH, (C) —CO—O—(C₁-C₄ alkyl), (D) —OH, or(E) C₁-C₆ alkoxy, (IV) —(CH₂)₂ ₆—OH, (V)—(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl) where R_(C−x) and R_(C−y) are —H, C₁-C₄alkyl and φ- and R_(C-aryl) is the same as R_(N-aryl), (VI)(CH₂)₀₋₄—R_(C-heteroaryl) where R_(C-heteroaryl) is: (A) pyridinyl, (B)pyrimidinyl, (C) quinolinyl, (D) indenyl, (E) indanyl, (F)benzothiophenyl, (G) indolyl, (H) indolinyl, (I) pyridazinyl, (J)pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M) quinazolinyl, (N)quinoxalinyl, (O) phthalazinyl, (P) isoxazolyl, (Q) pyrazolyl, (R)indolizinyl, (S) indazolyl, (T) benzothiazolyl, (U) benzimidazolyl, (V)benzofuranyl, (W) furanyl, (X) thienyl, (Y) pyrrolyl, (Z) oxadiazolyl,(AA) thiadiazolyl, (BB) triazolyl, (CC) tetrazolyl, (DD) 1,4-benzodioxan(EE) purinyl, (FF) oxazolopyridinyl, (GG) imidazopyridinyl, (HH)isothiazolyl, (II) naphthyridinyl, (JJ) cinnolinyl, (KK) carbazolyl,(LL) P-carbolinyl, (MM) isochromanyl, (NN) chromanyl, (OO) furazanyl,(PP) tetrahydroisoquinoline, (QQ) isoindolinyl, (RR)isobenzotetrahydrofuranyl, (SS) isobenzotetrahydrothienyl, (TT)isobenzothiophenyl, (UU) benzoxazolyl, or (VV) pyridopyridinyl, (VII )—(CH₂)₀₋₄—R_(C-heterocycle) where R_(C-heterocycle) is the same asR_(1-heterocycle), (VIII) —C(R_(C−1))(R_(C−2))—CO—NH-R_(C−3) whereR_(C−1) and R_(C−2) are the same or different and are: (A) —H, (B)—C₁-C₆ alkyl, (C) —(C₁-C₄ alkyl)-R_(C′-aryl) where R_(C′-aryl) is asdefined above for R_(1-aryl), (D) —(C₁-C₄ alkyl)-R_(C-heteroaryl) whereR_(C-heteroaryl) is as defined above, (E) —(C₁-C₄alkyl)-R_(C-heterocycle) where R_(C-heterocycle) is as defined above,(F) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above, (G)—R_(C-heterocycle) where R_(C-heterocycle) is as defined above, (H)—(CH₂)₁₋₄—OH, (I) —(CH₂)₁₋₄—R_(C−4)—(CH₂)₁₋₄—R_(C′-aryl) where R_(C−4)is —O—, —S—, —NH— or —NHR_(C−5)- where R_(C−5) is C₁-C₆ alkyl, and whereR_(C′-aryl) is as defined above, (J)—(CH₂)₁₋₄—R_(C−4)—(CH₂)₁₋₄—R_(C-heteroaryl) where R_(C−4) andR_(C-heteroayl) are as defined above, or (K) —R_(C′-aryl) whereR_(C′-aryl) is as defined above, and where R_(C−3) is: (A) —H, (B)—C₁-C₆ alkyl, (C) —R_(C′-aryl) where R_(C′-aryl) is as defined above,(D) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above, (E)—R_(C-heterocycle) where R_(C-heterocycle) is as defined above, (F)—(C₁-C₄ alkyl)-R_(C-aryl) where R_(C′-aryl), is as defined above, (G)—(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is as definedabove, or (H) —(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle)is as defined above, (IX) —CH(φ)₂, (X) -cyclopentyl or -cyclohexyl ringfused to a phenyl or heteroaryl ring where heteroaryl is as definedabove and phenyl and heteroaryl are unsubstituted or substituted withone, two or three: (A) C₁-C₃ alkyl, (B) —CF₃, (C) —F, Cl, —Br and —I,(D) C₁-C₃ alkoxy, (E) —OCF₃, (F) —NH₂, (G) —OH, or (H) —C≡N, (XI)—CH₂—C≡CH; (XII) —(CH₂)₀₋₁ —CHR_(C−5)-(CH₂)₀₋₁-φ where R_(C−5) is: (A)—OH, or (B)—CH₂—OH; (XIII) —CH(-φ)—CO—O(C₁-C₃ alkyl); (XIV)—CH(—CH₂—OH)—CH(—OH)—<—NO₂; (XV) —(CH₂)₂—O—(CH₂)₂—OH; (XVI)—CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; (XVII) —(C₂-C₈) alkynyl; or (XVIII) —H; ora pharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 where R₁ is: (V) —(CH₂)₀₋₃-(R_(1-aryl)), or (VI)—(CH₂)_(n1)-(R_(1-heteroaryl)) where RN is: (I) R_(N-1)-X_(N)- whereX_(N) is: (A) —CO—, or (B) —S0₂—, where R_(N-1) is: (A) R_(N-aryl), or(B) —R_(N-heteroaryl), (VI)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl)) whereR_(C) is: (I)—C₁-C₈ alkyl, (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkyl, (IV)—(CH₂)₀₋₃—OH, (V) —(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI)—(CH₂)₀₋₄—R_(C-heteroaryl), (VII) —(CH₂)₀₋₄—R_(C-heterocycle), (VIII)—C(R_(C−1))(R_(C−2))—CO—NH—R_(C−3), or (X) -cyclopentyl or -cyclohexylring fused to a phenyl or heteroaryl ring where heteroaryl is as definedabove and phenyl and heteroaryl are unsubstituted or substituted withone or two: (A) C₁-C₃ alkyl, 2(B) —CF₃, (C) —F, Cl, —Br or—I, (D) C₁-C₃alkoxy, or (E) —OCF₃.
 3. A compound according to claim 2 where R₁ is:(V) —CH₂-(R_(1-aryl)), or (VI) —CH₂-(R_(1-heteroaryl)); where R₂ is —H;where R_(N) is: (I) R_(N-1) X_(N-) where X_(N) is: (A) —CO—, whereR_(N-1) is: (A) R_(N-aryl), or (B) RN-heteroaryl, where R_(C) is: (III)—(CH₂)₀₋₃-(C₃-C₇) cycloalkyl, (V) —(CR_(C−x)R_(C−y))0-4—R_(C-aryl), (VI)—(CH₂)₀₋₄—R_(C-heteroaryl), (VII) —(CH₂)₀₋₄—R_(C-heterocycle), (VIII)—C(R_(C−1))(R_(C−2))—CO—NH—R_(C−3), or (X) -cyclopentyl or -cyclohexylring fused to a phenyl or heteroaryl ring.
 4. A compound according toclaim 3 where R_(C) is: (V) —(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI)—(CH₂)₀₋₄—R_(C-heteroaryl), or (X) -cyclopentyl or -cyclohexyl ringfused to a phenyl or heteroaryl ring.
 5. A compound according to claim 1where R₁ is —CH₂-(R_(1-aryl)) where R_(1-aryl) is phenyl.
 6. A compoundaccording to claim 1 where R₁ is —CH₂-(R_(1-aryl)) where R_(1-aryl) isphenyl substituted with two —F.
 7. A compound according to claim 6 wherephenyl is substituted with two —F in the 3-and 5- positions giving3,5-difluorophenyl.
 8. A compound according to claim 1 where R₂ is: (I)—H, (II) C₁-C₆ alkyl, or (III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl).9. A compound according to claim 1 where R₂ is: (II) C₁-C₆ alkyl, or(III) benzyl.
 10. A compound according to claim 1 where R_(N) is:R_(N-1)-X_(N)- where X_(N) is —CO—, where R_(N-1) is R_(N-aryl) whereR_(N-aryl) is phenyl substituted with one —CO—NR_(N-2)R_(N-3)where thesubstitution on phenyl is 1,3-.
 11. A compound according to claim 10where R_(N-2) and R_(N-3) are the same and are C₃ alkyl.
 12. A compoundaccording to claim 1 where R_(N) is: R_(N-1)-X_(N)— where X_(N) is —CO—,where R_(N-1) is R_(N-aryl), where R_(N-aryl), is phenyl substitutedwith one C₁ alkyl and with one —CO—NR_(N-2)RN₃ where the substitution onthe phenyl is 1,3,5-.
 13. A compound according to claim 12 where R_(N-2)and R_(N-3) are the same and are C₃ alkyl.
 14. A compound according toclaim 1 where R_(N) is R_(N-1)-X_(N)- where X_(N i)s —CO—, where R_(N-1)is R_(N-heteroaryl) where R_(N-heteroaryl) is substituted with one—CO—NR_(N-2)R_(N-3).
 15. A compound according to claim 14 where R_(N-2)and R_(N-3) are the same and are —C₃ alkyl.
 16. A compound according toclaim 1 where R_(N) is: A—X_(N)- where X_(N) is —CO—, where A is: (C)C₁₀H₇—CH(OH)—, or (D) t-butoxy.
 17. A compound according to claim 1where R_(C) is: (V) —(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI)—(CH₂)₀₋₄—R_(C-heteroaryl), (VII) —(CH₂)₀₋₄—R_(C-heterocycle), (X)-cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroaryl ringwhere heteroaryl is as defined above and phenyl and heteroaryl areunsubstituted or substituted with one or two: (A) C₁-C₃ alkyl, (B) —CF₃,(C) —F, Cl, —Br or —I, (D) C₁-C₃ alkoxy, (E) —OCF₃, or (XVIII) —H.
 18. Acompound according to claim 17 where Rc is: (V)—(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl) where R_(C-aryl) is phenyl.
 19. Acompound according to claim 18 where phenyl substituted in the3-position or 3,5-positions.
 20. A compound according to claim 17 whereR_(C) is: (VI) —CH₂—R_(C-heteroaryl),
 21. A compound according to claim17 where R_(C) is: (VII) —CH₂—R_(C-heterocycle).
 22. A compoundaccording to claim 17 where R_(C) is: (X) -cyclohexyl ring fused to aphenyl ring.
 23. A compound according to claim 1 where R_(C) is: (I)—(C₁-C₁₀)alkyl-K₁₋₃ where each K is: (1) H, (11) carboxyl, (16) aminounsubstituted or substituted with C₁-C₆ alkyl; or (18) carboxyl methylester; (II) —(CH₂)₀₋₃-J-[-K]₁₋₃, where J is: (A) a 5 to 7 atommonocyclic aryl group, or (B) a 5 to 10 atom multicyclic cycloalkylgroup, and each K is: (1) H, (3) C₁-C₃ alkoxy, or (11) carboxyl, (III)—(CH₂)₀₋₃-(C₃-C₇) cycloalkyl where cycloalkyl can be unsubstituted orsubstituted with one, two or three: (B) —CO—OH, (C) —CO—O—(C₁-C₄ alkyl),or (E) C₁-C₆ alkoxy, (IV) —(CH₂)₂₋₆—OH, (V) —(CH₂)₀₋₄—R_(C-aryl), (VI)—(CH₂)₀₋₄—R_(C-heteroaryl), (VII) —(CH₂)₀₋₄—R_(C-heterocycle), or(XVIII) —(C₂-C₈) alkynyl.
 24. A compound according to claim 23 whereR_(C) is: (I) —(C₁-C₁₀)alkyl-K where K is H, carboxyl, carboxyl methylester, amino unsubstituted or substituted with C₁-C₆ alkyl, (II) abenzyl or phenylpropyl group substituted with a carboxyl group, (III)—(CH₂)₀₋₃-(C₃-C₇) cycloalkyl where cycloalkyl is cyclohexyl, cyclohexylsubstituted with 1 or 2 carboxyl groups, or cyclohexyl substituted with1 or 2 alkoxy groups, (V) —(CH₂)0-4-phenyl substituted or unsubstitutedwith F, (VI) —(CH₂)₀₋₄-heteroaryl, or (VII) selected from—(CH₂)₀₋₄-morpholinyl and —(CH₂)₀₋₄-tetrahydrofuryl.
 25. A compoundaccording to claim 24 where R_(C) is: (I) C₅H₁₀-K or C₇H₁₄-K where K iscarboxyl or carboxyl methyl ester, (II) a benzyl or phenylpropyl groupsubstituted with a carboxyl group at the 5-position, or (III) acyclohexyl ring substituted at the 3- and 5- positions or at the4-position with a carboxyl group.
 26. A compound according to claim 1where R₁ is: (I) C₁-C₅ alkyl, (II) —(CH₂)₁ ₂—S—CH₃, (IV) C₁-C₅ alkenyl,(V) —(CH₂)₀₋₃-(Rl,aryl) where R_(1-aryl) is as defined above, and (VI)—(CH₂) ₀₋₃-(R_(1-heteroary)) where R_(1-heteroaryl) is as defined above,wherein any of the above are unsubstituted or substituted with up to twoC₁-C₃ alkyl, —F, —Cl, —Br, —I, or —CF₃; where R₂ is: (I) —H (II) C₁-C₆alkyl, or (III) —(CH₂)₀₋₃-R₂₋₁ where R₂₋₁ is (C₃-C₆)cycloalkyl,R_(1-aryl) or R_(1-heteroaryl) where R_(1-aryl) is a 5 or 6-memberedaryl group and R_(1-heteroary), is as defined above; where R_(N) is:(II) A-X_(N)- where X_(N) is —CO—, wherein A is (A) —T-E—(Q)_(m′), (1)where —T is

where (a) x=1 when y=1 and x=2 when y=0, (b) m is 0, 1, 2 or 3, (c) thevalues of x and y vary independently on each carbon when m is 2 and 3,and (d) R′″ varies independently on each carbon and is H, (C₁-C₂) alkyl,phenyl, or phenyl(C₁-C₃)alkyl; (2) -E is (a) C₁-C₅ alkyl, but only if m′does not equal 0, (b) methylthioxy(C₂-C₄)alkyl, (c) an aryl group having5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (d) aheterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12atoms when fused, (e) a mono or fused ring cycloalkyl group having 5 to10 carbon atoms, (f) biphenyl, (g) diphenyl ether, (h) diphenylketone,(i) phenyl(C₁-C₈)alkyloxyphenyl, or (j) C₁-C₆ alkoxy; (3) —Q is (a)C₁-C₃ alkyl, (b) C₁-C₃ alkoxy, (c) C₁-C₃ alkylthioxy, (d) C₁-C₆alkylacylamino, (e) C₁-C₆ alkylacyloxy, (f) amido (including primary,C₁-C₆ alkyl and phenyl secondary and tertiary amino moieties), (g) C₁-C₆alkylamino (h) phenylamino, (i) carbamyl (including C₁-C₆ alkyl andphenyl amides and esters), (j) carboxyl (including C₁-C₆ alkyl andphenyl esters), (k) carboxy(C₂-C₅)alkoxy, (l) carboxy(C₂-C₅)alkylthioxy,(m) heterocyclylacyl, (n) heteroarylacyl, or (o) hydroxyl; (4) m′ is 0,1, 2 or 3; (B) -E(Q)_(m″) wherein E and —Q are as defined as above andm″ is 0, 1, 2, or 3; (C) —T-E wherein -E and —Q are as defined as above;or (D) -E wherein -E is as defined as above; where R_(C) is: (I)—(C₁-C₁₀)alkyl-K₁₋₃ (E) the alkyl chain optionally contains acombination of up to three atoms of oxygen and sulfur each such atomreplacing one carbon, (F) each K is: (2) C₁-C₃ alkyl, (3) C₁-C₃ alkoxy,(4) C₁-C₃ alkylthioxy, (5) C₁-C₆ alkylacylamino, (6) C₁-C₆ alkylacyloxy,(7) amido, (8) C₁-C₆ alkylamino (9) phenylamino, (10) carbamyl, (11)carboxyl, (12) carboxy(C₂-C₅)alkoxy, (13) carboxy(C₂-C₅)alkylthioxy,(14) heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted orsubstituted with C₁-C₆ alkyl, (17) hydroxyl, or (18) carboxyl methylester; (II) —(CH₂)₀₋₃-J-[(-(CH₂)₀₋₃-K]₁₋₃ where K is: (2) C₁-C₃ alkyl,(3) C_(l)-C₃ alkoxy, (4) C₁-C₃ alkylthioxy, (5) C₁-C₆ alkylacylamino,(6) C₁-C₆ alkylacyloxy, (7) amido, (8) C₁-C₆ alkylamino (9) phenylamino,(10) carbamyl, (11) carboxyl, (12) carboxy(C₂-C₅)alkoxy, (13)carboxy(C₂-C₅)alkylthioxy, (14) heterocyclylacyl, (15) heteroarylacyl,(16) amino unsubstituted or substituted with C₁-C₆ alkyl, (17) hydroxyl,or (18) carboxyl methyl ester; J is: (A) a 5 to 7 atom monocyclic arylgroup, (B) a 8 to 12 atom multicyclic aryl group, (C) a 5 to 7 atommonocyclic heterocyclic group, (D) a 8 to 12 atom multicyclicheterocyclic group, or (E) a 5 to 10 atom monocyclic or multicycliccycloalkyl group; and where B is O or NH.
 27. A compound according toclaim 1 where the pharmaceutically acceptable salt is a salt ofhydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric,citric, methanesulfonic, CH₃-(CH₂)_(n)—COOH where n is 0 tluu 4,HOOC-(CH₂)n—COOH where n is as defined above, HOOC—CH═CH—COOH and φ—COOHacid or triethanolamine, N-methylglucamine, diethanolamine,ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, orcarbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali oralkaline earth metal.
 28. A compound according to claim 1 which is:N-[(1S, 2S, 4R)-1-(3,5-Difluorobenzyl)-4-(syn,syn)-(3,5-dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide,6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoicacid,5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoicacid,4-L6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyricacid,3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionicacid,8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoicacid, 8-[6-(3,5 -Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoicacid methyl ester, N-[4-(R)-Butylcarbamoyl- 1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide,N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine- 1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-NN-dipropyl-isophthalamide, 4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid methyl ester, N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid, 4-(anti)-([6-(3,5 -Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-⁴-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid, 4-(anti)-([6-(3,5 -Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid methyl ester, N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,or N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide.29. A compound according to claim 1 which is:


30. A compound of the formula

where R₁ is: (V) —CH₂-phenyl, where phenyl is substituted with two —F inthe 3- and 5-positions giving 3, 5-difluorophenyl, or (VI)—(CH₂)_(n1)-(R_(1-heteroaryl) where n1 and R_(1-heteroaryl) are asdefined above; and PROTECTING GROUP is t-butoxycarbonyl,benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl,chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-l-enyloxycarbonyl,5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobornyloxycarbonyl, -phenyl-C(═N)—H, or 1-piperidyloxycarbonyl.
 31. Acompound according to claim 30 where where R₁ is —CH₂-phenyl, wherephenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
 32. A compound according to claim 30 where PROTECTINGGROUP is t-butoxycarbonyl.
 33. A compound according to claim 30 wherePROTECTING GROUP is benzyloxycarbonyl.
 34. A compound according to claim30 which is:(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carbamicacid tert-butyl ester, (L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamicacid tert-butyl ester, (L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acidtert-butyl ester,(L)-[2-(3,5-Difluorophenyl)-1-(methoxymethylcarbamoyl)-ethyl]-carbamicacid benzyl ester, (L)-[1-(3,5-Difluorobenzyl)-2-oxoethyl]-carbamic acidbenzyl ester, or (L)-[1-(3,5-Difluorobenzyl)allyl]-carbamic acid benzylester.
 35. An epoxide compound of the formula

where R₁ is: (A) —CH₂-φ where -φ is substituted with two —F, (B)—(CH₂)_(n1)—R_(1-heteroaryl) where n₁ is 0, 1, 2, or 3 and R₁ heteroary,is: (A) pyridinyl, (B) pyrimidinyl, (C) quinolinyl, (D) indenyl, (E)indanyl, (F) benzothiophenyl, (G) indolyl, (H) indolinyl, (I)pyridazinyl, (J) pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M)quinazolinyl, (N) quinoxalinyl, (O) phthalazinyl, (P) imidazolyl, (Q)isoxazolyl, (R) pyrazolyl, (S) oxazolyl, (T) thiazolyl, (U) indolizinyl,(V) indazolyl, (W) benzothiazolyl, (X) benzimidazolyl, (Y) benzofuranyl,(Z) furanyl, (AA) thienyl, (BB) pyrrolyl, (CC) oxadiazolyl, (DD)thiadiazolyl, (EE) triazolyl, (FF) tetrazolyl, (GG) 1,4-benzodioxan (HH)purinyl, (II) oxazolopyridinyl, (JJ) imidazopyridinyl, (KK)isothiazolyl, (LL) naphthyridinyl, (MM) cinnolinyl, (NN) carbazolyl,(OO) P-carbolinyl, (PP) isochromanyl, (QQ) chromanyl, (RR) furazanyl,(SS) tetrahydroisoquinoline, (TT) isoindolinyl, (UU)isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl, (C)—(CH₂)_(n1)—R_(1-heterocycle) where n₁ is 0, 1, 2, or 3 andR_(1-heterocycle) is: (A) morpholinyl, (B) thiomorpholinyl, (C)thiomorpholinyl S-oxide, (D) thiomorpholinyl S,S-dioxide, (E)piperazinyl, (F) homopiperazinyl, (G) pyrrolidinyl, (H) pyrrolinyl, (I)tetrahydropyranyl, (J) piperidinyl, (K) tetrahydrofuranyl, or (L)tetrahydrothiophenyl, and PROTECTING GROUP is t-butoxycarbonyl,benzyloxycarbonyl, formyl, trityl, phthalimido, trichloroacetyl,chloroacetyl, bromoacetyl, iodoacetyl, 4-phenylbenzyloxycarbonyl,2-methylbenzyloxycarbonyl, 4-ethoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,3-chlorobenzyloxycarbonyl, 2-cblorobenzyloxycarbonyl,2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,4-cyanobenzyloxycarbonyl, 2-(4-xenyl)isopropoxycarbonyl,1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl,cyclopentanyloxycarbonyl, 1-methylcycoopentanyloxycarbonyl,cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl,2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl,fluorenylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-l-enyloxycarbonyl,5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobornyloxycarbonyl, -phenyl—C(═N)—H, or 1-piperidyloxycarbonyl.
 36. Anepoxide compound of formula (VI) according to claim 35 where R₁ is: (B)—(CH₂)_(n1)-(R_(1-heteroaryl)).
 37. An epoxide compound of formula (VI)according to claim 36 where n, is
 1. 38. An epoxide compound of formula(VI) according to claim 35 where R₁ is: (C)—(CH₂)_(n1)-(R_(1-heterocycle)).
 39. An epoxide compound of formula (VI)according to claim 38 where n₁ is
 1. 40. An epoxide compound of formula(VI) according to claim 35 where phenyl is substituted in the 3- and 5-positions giving 3,5-difluorophenyl.
 41. An epoxide compound of formula(VI) according to claim 35 where PROTECTING GROUP is t-butoxycarbonyl.42. An epoxide compound of formula (VI) according to claim 35 wherePROTECTING GROUP is benzyloxycarbonyl.
 43. An epoxide compound offormula (VI) according to claim 35 which is (1S,2R)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamic acid tert-butylester, or (1S, 2R)-[2-(3,5-Difluorophenyl)-1-oxiranylethyl]-carbamicacid benzyl ester.
 44. A compound of formula

where R₁ is: (V) —CH₂-phenyl, where phenyl is substituted with two —F inthe 3- and 5-positions giving 3,5-difluorophenyl, or (VI)—(CH₂)_(n1)-(R_(1-heteroaryl)), where n1 and R_(1-heteroaryl) are asdefined above; where R₂ is as defined in claim 1; and PROTECTING GROUPis t-butoxycarbonyl, benzyloxycarbonyl, formyl, trityl, phthalimido,trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl,4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl,4-ethoxybenzyloxycarbonyl, 4-fluorobenzylxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, 2,4-dchlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl,2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl,1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl,2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl,l-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl,2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,5-benzisoxazoylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,isobomyloxycarbonyl, -phenyl—C(═N)—H, or 1-piperidyloxycarbonyl.
 45. Acompound according to claim 44 where where R₁ is —CH₂-phenyl, wherephenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
 46. A compound according to claim 44 where PROTECTINGGROUP is t-butoxycarbonyl.
 47. A compound according to claim 44 wherePROTECTING GROUP is benzyloxycarbonyl.
 48. A compound according to claim44 where R₂ is —H.
 49. A compound according to claim 44 where R₂ isC₁-C₆ alkyl.
 50. A compound according to claim 44 which is: (1S,2S,4R)-[1 -(3,5-Difluorobenzyl)-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamicacid tert-butyl ester,[2-(3,5-Difluorophenyl)-1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2-(S)-yl)-ethyl]-carbamicacid tert-butyl ester, (1S,2S, 4R)-[1 -(3,5-Difluorobenzyl)-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3aH-indeno[1,2-d]oxazole-3-carbonyl)-2-hydroxyhexyl]-carbamicacid benzyl ester, or [2-(3,5-Difluorophenyl)- 1-(S)-(4-(R)-ethyl-5-oxo-tetrahydrofuran-2-(S)-yl)-ethyl]-carbamic acid benzyl ester.
 51. Acompound of formula

where R₁ is: (V) —CH₂-phenyl, where phenyl is substituted with two —F inthe 3- and 5-positions giving 3, 5-difluorophenyl, or (VI)—(CH2)_(n1)—R_(1-heteroaryl)), where n1 and R_(1-heteroaryl) are asdefined above; and where R₂ is as defined in claim
 1. 52. A compoundaccording to claim 51 where where R₁ is —CH₂-phenyl, where phenyl issubstituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
 53. A compound according to claim 51 where PROTECTINGGROUP is t-butoxycarbonyl.
 54. A compound according to claim 51 wherePROTECTING GROUP is benzyloxycarbonyl.
 55. A compound according to claim51 where R₂ is —H.
 56. A compound according to claim 51 where R₂ isC₁-C₆ alkyl.
 57. A compound according to claim 51 which is5S-[1S-Amino-2-(3,5-difluorophenyl)ethyl]-3R-ethyldihydrofuran-2-one.58. A compound of formula

where R₁, R₂ and R_(N) are as defined in claim
 1. 59. A compoundaccording to claim 58 where R₁ is: (I) C₁-C₆ alkyl (V)—(CH₂)₀₋₁-(R_(1-aryl)), or (VI) (CH₂)_(n1)-(R_(1-heteroaryl)).
 60. Acompound according to claim 59 where R₁ is —(CH₂)-(R_(1-aryl)) whereR_(1-aryl) is phenyl.
 61. A compound according to claim 60 where phenylis substituted with one, two or three —F, —Cl, —Br and —I.
 62. Acompound according to claim 61 where phenyl is substituted with two -F63. A compound according to claim 62 where phenyl is substituted withtwo -F in the 3- and 5- positions giving 3,5-difluorophenyl.
 64. Acompound according to claim 58 where R₂ is —H.
 65. A compound accordingto claim 58 where R₂ is C₁-C₆ alkyl.
 66. A compound according to claim58 where R₂ is —(CH₂)R_(1-aryl) where R_(1-aryl) is phenyl.
 67. Acompound according to claim 58 where PROTECTING GROUP ist-butoxycarbonyl.
 68. A compound according to claim 58 where PROTECTINGGROUP is benzyloxycarbonyl.
 69. A compound according to claim 58 whereR_(N) is: (I) RN_(N-1)—X_(N)— where X_(N) is: (A) —CO—, or (B) —SO₂-,where R_(N-1) is: (A) R_(N-aryl) or (B) —R_(N-heteroaryl), (V)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂R_(N-aryl)/R_(N-heteroaryl)).
 70. Acompound according to claim 69 where R_(N) is: (I) R_(N-1 -X) _(N)-where X_(N) is (A) —CO—, where R_(N-1) is: (A) R_(N-aryl), and (B)—R_(N-heteroaryl).
 71. A compound according to claim 70 where R_(N) is:(a) R_(N-1)-X_(N)— where X_(N) is —CO—, where R_(N-1) is R_(N-aryl),where R_(N-aryl) is phenyl substituted with one —CO—NR_(N-2)R_(N-3)wherethe substitution on phenyl is 1,3- and where R_(N-2) and R_(N-3) are thesame and are C₃ alkyl (b) R_(N-1)-X_(N)— where X_(N) is —CO—, whereR_(N-1) is R_(N-aryl), where R_(N-aryl) is phenyl substituted with oneC₁ alkyl and with one —CO—NR_(N-2)R_(N-3)where the substitution on thephenyl is 1,3,5- and where R_(N-2) and R_(N-3) are the same and are C₃alkyl.
 72. A compound according to claim 58 which isN-{2-(3,5-Difluorophenyl)-(1S, 2S,4R)-[1-(4-ethyl-5-oxotetrahydrofuran-2-yl)]ethyl}-N′,N′-dipropylisophthalamide.73. A method of treating or preventing a disease or condition selectedfrom Alzheimer's disease, mild cognitive impairment, Down's syndrome,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type,cerebral amyloid angiopathy, degenerative dementia, diffuse Lewy bodytype of Alzheimer's disease or central or preipheral amyloid diseases ina patient who is in need of such treatment which comprisesadministration to said patient a therapeutically effective amount of ahydroxyethylene compound of the formula

where R₁ is: (I) C₁-C₆ alkyl, unsubstituted or substituted with one, twoor three C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —NH₂, —C≡N, —CF₃, or —N₃,(II) —(CH₂)₁₋₂—S—CH₃, (III) —CH₂—CH₂—S—CH₃, (IV) —CH₂-(C₂-C₆ alkenyl)unsubstituted or substituted by one —F, (V) —(CH₂)₀₋₃-(R_(1-aryl)) whereR_(1-aryl) is phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl,dihydronaphthyl, tetralinyl unsubstituted or substituted on the arylring with one or two of the following substituents which can be the sameor different: (A) C₁-C₃ alkyl, (B) —CF₃, (C) —F, Cl, —Br and —I, (D)C₁-C₃ alkoxy, (E) —O—CF₃, (F) —NH₂, (G) —OH, or (H) —C≡N, (VI)(CH₂)_(n1)-(R_(1-heteroaryl)) where n₁ is 0, 1, 2, or 3 andR_(1-heteroaryl) is: (A) pyridinyl, (B) pyrimidinyl, (C) quinolinyl, (D)indenyl, (E) indanyl, (F) benzothiophenyl, (G) indolyl, (H) indolinyl,(I) pyridazinyl, (J) pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M)quinazolinyl, (N) quinoxalinyl, (O) phthalazinyl, (P) imidazolyl, (Q)isoxazolyl, (R) pyrazolyl, (S) oxazolyl, (T) thiazolyl, (U) indolizinyl,(V) indazolyl, (W) benzothiazolyl, (X) benzimidazolyl, (Y)benzofuiranyl, (Z) firanyl, (AA) thienyl, (BB) pyrrolyl, (CC)oxadiazolyl, (DD) thiadiazolyl, (EE) triazolyl, (FF) tetrazolyl, (GG)1,4-benzodioxan (HH) purinyl, (II) oxazolopyridinyl, (JJ)imidazopyridinyl, (KK) isothiazolyl, (LL) naphthyridinyl, (MM)cinnolinyl, (NN) carbazolyl, (OO) P-carbolinyl, (PP) isochromanyl, (QQ)chromanyl, (RR) fuirazanyl, (SS) tetrahydroisoquinoline, (TT)isoindolinyl, (UU) isobenzotetrahydrofuranyl, (VV)isobenzotetrahydrothienyl, (WW) isobenzothiophenyl, (XX) benzoxazolyl,or (YY) pyridopyridinyl, where the R_(1-heteroaryl) group is bonded to—(CH₂)₀₋₃- by any ring atom of the parent R_(N-heteroaryl) groupsubstituted by hydrogen such that the new bond to the R_(1-heteroaryl)group replaces the hydrogen atom and its bond, where heteroaryl isunsubstituted or substituted with one or two: (1) C₁-C3 alkyl, (2) —CF₃,(3) —F, Cl, —Br, or —I, (4) C₁-C₃ alkoxy, (5) —O—CF₃, (6) —NH₂, (7) —OH,or (8) —C≡N, with the proviso that when n, is zero R_(1-heteroaryl) isnot bonded to the carbon chain by nitrogen, or (VII)—(CH₂)_(n1)-(R_(1-heterocycle) where n) ₁ is as defined above andR_(1-heterocycle) is: (A) morpholinyl, (B) thiomorpholinyl, (C)thiomorpholinyl S-oxide, (D) thiomorpholinyl S,S-dioxide, (E)piperazinyl, (F) homopiperazinyl, (G) pyrrolidinyl, (H) pyrrolinyl, (I)tetrahydropyranyl, (J) piperidinyl, (K) tetrahydrofaranyl, or (L)tetrahydrothiophenyl, where the R_(1-heterocycle) group is bonded by anyatom of the parent R_(1-heterocycle) group substituted by hydrogen suchthat the new bond to the R_(1-heteroaryl) group replaces the hydrogenatom and its bond, where heterocycle is unsubstituted or substitutedwith one or two: (1) ═O, (2) C₁-C₃ alkyl, (3) —CF₃, (4) —F, Cl, —Br and—I, (5) C₁-C₃ alkoxy, (6) —O—CF₃, (7) —NH₂, (8) —OH, or (9) —C≡N, withthe proviso that when n₁ is zero R_(1-heterocycle) is not bonded to thecarbon chain by nitrogen; where R₂ is: (I) —H, (II) C₁-C₆ alkyl, or(III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is (C₃-C₆)cycloalkyl, R_(1-aryl) orR_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as definedabove, where R_(N) is: (I) R_(N-1)-X_(N)- where X_(N) is: (A) —CO—, (B)—SO₂—, (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and are—H or C₁-C₄ alkyl, (D) —CO—(CR′R″)₁₋₆-X_(N-1) where X_(N-1) is —O—, —S—and —NR′R″- and where R′ and R″ are as defined above, (E) a single bond;where R_(N-1) is: (A) R_(N-aryl) where R_(N-aryl), is phenyl, 1-naphthyland 2-naphthyl unsubstituted or substituted with one, two, three or fourof the following substituents which can be the same or different andare: (1) C₁-C₆ alkyl, (2) —F, —Cl, —Br, or —I, (3) —OH, (4) —NO₂, (5)—CO—OH, (6) —C≡N, (7) -CO-NR_(N-2) R_(N-3) where R_(N-2) and R_(N-3) arethe same or different and are: (a) —H, (b) —C₁-C₆ alkyl unsubstituted orsubstituted with one (i) —OH, or (ii) —NH₂, (c) —C₁-C₆ alkylunsubstituted or substituted with one to three -F, —Cl, —Br, or —I, (d)—C₃-C₇ cycloalkyl, (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), (f) —(C₁-C₆alkyl)-O—(C₁-C₃ alkyl), (g) —C₁-C₆ alkenyl with one or two double bonds,(h) —C₁-C₆ alkynyl with one or two triple bonds, (i) —C₁-C₆ alkyl chainwith one double bond and one triple bond, (j) —R_(1-aryl) whereR_(1-aryl) is as defined above, or (k) —R_(1-heteroaryl) whereR_(1-heteroaryl) is as defined above, (8) —CO—(C₃-C₁₂ alkyl), (9)—CO—(C₃-C₆ cycloalkyl), (10) —CO—Riheteroaryl where R_(1-heteroaryl) isas defined above, (11) —CO—R_(1-heterocycle) where R_(1-heterocycle) isas defined above, (12) —CO—R_(N-4) where R_(N-4) is morpholinyl,thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl where eachgroup is unsubstituted or substituted with one or two C₁—C₃ alkyl, (13)—CO—O—R_(N-5) where R_(N-5) is: (a) C₁-C₆ alkyl, or (b)—(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is defined above, (14)—SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are as defined above, (15)—SO—(C₁-C₈ alkyl), (16) —SO₂(C₃-C₁₂ alkyl), (17) —NH—CO—O—R_(N-5) whereR_(N-5) is as defined above, (18) —NH—CO—N(C₁-C₃ alkyl)₂, (19)—N—CS—N(C₁-C₃ alkyl)₂, (20) —N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) isas defined above, (21) —NR_(N-2) R_(N-3) where R_(N-2) and R_(N-3) canbe the same or different and are as defined above, (22) —R_(N-4) whereR_(N-4) is as defined above, (23) —O—CO—(C₁-C₆ alkyl), (24)—O—CO—N(C₁-C₃ alkyl)₂, (25) —O—CS—N(C-C₃ alkyl)₂, (26) —O—(C₁-C₆ alkyl),(27) —O—(C₂-C₅ alkyl)-COOH, (28) —S—(C₁-C₆ alkyl), (29) C₁-C₆ alkylunsubstituted or substituted with 1, 2, 3, 4, or 5 —F, (30) —O—(C₁-C₆alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —F, or (31) —O-φ, (B) —R_(N-heteroaryl) where R_(N-heteroaryl) is: (A) pyridinyl, (B)pyrimidinyl, (C) quinolinyl, (D) indenyl, (E) indanyl, (F)benzothiophenyl, (G) indolyl, (H) indolinyl, (I) pyridazinyl, (J)pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M) quinazolinyl, (N)quinoxalinyl, (O) phthalazinyl, (P) imidazolyl, (Q) isoxazolyt, (R)pyrazolyl, (S) oxazolyl, (T) thiazolyl, (U) indolizinyl, (V) indazolyl,(W) benzothiazolyl, (X) benzimidazolyl, (Y) benzofiuranyl, (Z) firanyl,(AA) thienyl, (BB) pyrrolyl, (CC) oxadiazolyl, (DD) thiadiazolyl, (EE)triazolyl, (FF) tetrazolyl, (GG) 1,4-benzodioxan (HH) purinyl, (II)oxazolopyridinyl, (JJ) imidazopyridinyl, (KK) isothiazolyl, (LL)naphthyridinyl, (MM) cinnolinyl, (NN) carbazolyl, (OO) β-carbolinyl,(PP) isochromanyl, (QQ) chromanyl, (RR) furazanyl, (SS)tetrahydroisoquinoline, (TT) isoindolinyl, (UU)isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl, wherethe R_(N-heteroryl) group is bonded by any atom of the parentR_(N-heteroaryl) group substituted by hydrogen such that the new bond tothe R_(N-heteroaryl) group replaces the hydrogen atom and its bond,where heteroaryl is unsubstituted or substituted with one or two: (1)C₁-C₆ alkyl, (2) —F, —Cl, —Br, or —I, (3) —OH, (4) —NO₂, (5) —CO—OH, (6)—CN, (7) —CO—NR_(N-2) R_(N-3) where R_(N-2) and R_(N-3) are the same ordifferent and are: (a) —H, (b) —C₁-C₆ alkyl unsubstituted or substitutedwith one (i) —OH, or (ii) —NH₂, (c) —C₁-C₆ alkyl unsubstituted orsubstituted with 1, 2, or 3 —F, —Cl, —Br, or —I, (d) —C₃-C₇ cycloalkyl,(e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), (f) —(C₁-C₆ alkyl)-O—(C₁-C₃alkyl), (g) —C₁-C₆ alkenyl with one or two double bonds, (h) —C₁-C₆alkynyl with one or two triple bonds, (i) —C₁-C₆ alkyl chain with onedouble bond and one triple bond, (j) —R_(1-aryl) where R_(1-aryl) is asdefined above, or (k) R_(1-heteroaryl) where R_(1-heteroaryl) is asdefined above, (8) —CO—(C₃-C₁₂ alkyl), (9) —CO—(C₃-C₆ cycloalkyl), (10)—CO—R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (11)—CO—R_(1-hetercycle) where R_(1-heterocycle) is as defined above, (12)—CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl or pyrrolidinyl where each group is unsubstituted orsubstituted with one or two C₁-C₃ alkyl, (13) —CO—O—R_(N-5) whereR_(N-5) is: (a) C₁-C₆ alkyl, or (b) —(CH₂)₀₋₂-(R_(1-aryl)) whereR_(1-aryl) is as defined above, (14) —SO₂—NR_(N-2)R_(N-3)where R_(N-2)and R_(N-3) are as defined above, (15) —SO—(C₁-C₈ alkyl), (16)—SO2(C₃-C₁₂ alkyl), (17) —NH—CO—O—R_(N-5) where RN—S is as definedabove, (18) —NH—CO—N(C₁-C₃ alkyl)₂, (19) —N—CS—N(C₁-C₃ alkyl)₂, (20)—N(C₁-C₃ alkyl)-CO—RN₅ where R_(N-5) is as defined above, (21) —NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can be the same or different and areas defined above, (22) —R_(N-4) where R_(N-4) is as defined above, (23)—O—CO—(C₁-C₆ alkyl), (24) —O—CO—N(C₁-C₃ alkyl)₂, (25) —O—CS—N(C₁-C₃alkyl)₂, (26) —O—(C₁-C₆ alkyl), (27) —O—(C₂-C₅ alkyl)-COOH, or (28)—S—(C₁-C₆ alkyl), (C) —R_(N-aryl) where —R_(N-aryl), is as definedabove, (D) —R_(N-aryl)-R_(N-heteroaryl) where —R_(N-aryl) and—R_(N-heteroaryl) are as defined above, (E) —R_(N-heteroaryl)—R_(N-aryl)where —R_(N-aryl) and —R_(N-heteroaryl) are as defined above, (F)—R_(N-heteroaryl)—R_(N-heteroaryl) where R_(N-heteroaryl) is as definedabove, (G) —R_(N-aryl)-OR_(N-aryl), where —R_(N-aryl) is as definedabove, (H) R_(N-aryl)—S—R_(N-aryl) where —R_(N-aryl) is as definedabove, (I) R_(N-heteroaryl)-O—R_(N-heteroaryl) where R_(N-heteroaryl) isas defined above, (J) —R_(N-heteroaryl)—S—R_(N-heteroaryl) whereR_(N-heteroaryl) is as defined above, (K) R_(N-aryl)—CO—R_(N-aryl) where—R_(N-aryl) is as defined above, (L) R_(N-aryl)—COR—R_(N-heteroaryl)where —R_(N-aryl) and R_(N-heteroaryl) are as defined above, (M)—R_(N-aryl)—SO₂—R_(N-aryl) where R_(N-aryl) is as defined above, (N)R_(N-heteroaryl)—CO—R_(N-heteroaryl) where R_(N-heteroaryl) is asdefined above, (O) R_(N-heteroaryl)—SO₂R_(N-heteroaryl) whereR_(N-heteroaryl) is as defined above, (P) —R_(N-aryl)-O—(C₁-C₈ alkyl)-φwhere R_(N-aryl) is as defined above, (Q) —R_(N-aryl)—S—(C₁-C₈ alkyl)-φwhere R_(N-aryl) is as defined above, (R)—R_(N-heteroary)—O—(C₁-C₈alkyl)-φ where R_(N-heteroaryl) is as definedabove, or (S) —R_(N-heteroayl)—S—(C₁-C₈ alkyl)-φ where R_(N-heteroaryl)is as defined above, (II) A—XN— where XN is —CO—-, wherein A is (A)—T-E—(Q)_(m′), (1) where —T is

where (a) x=1 when y=1 and x=2 when y=0, (b) m is 0, 1, 2 or 3, (c) thevalues of x and y vary independently on each carbon when m is 2 and 3,and (d) R′″ varies independently on each carbon and is H, (C₁-C₂) alkyl,phenyl, or phenyl(C₁-C₃)alkyl; (2) -E is (a) Cl -C₅ alkyl, but only ifm′ does not equal 0, (b) methylthioxy(C₂-C₄)alkyl, (c) an aryl grouphaving 5 to 7 atoms when monocyclic or having 8 to 12 atoms when fuised,(d) a heterocyclic group having 5 to 7 atoms when monocyclic or having 8to 12 atoms when fused, (e) a mono or filsed ring cycloalkyl grouphaving 5 to 10 carbon atoms, (f) biphenyl, (g) diphenyl ether, (h)diphenylketone, (i) phenyl(C₁-C₈)alkyloxyphenyl, or (j) C₁-C₆ alkoxy;(3) —Q is (a) C₁-C₃ alkyl, (b) C₁-C₃ alkoxy, (c) C₁-C₃ alkylthioxy, (d)C₁-C₆ alkylacylamino, (e) C₁-C₆ alkylacyloxy, (f) amido (includingprimary, C₁-C₆ alkyl and phenyl secondary and tertiary amino moieties),(g) C₁-C₆ alkylamino (h) phenylamino, (i) carbamyl (including C₁-C₆alkyl and phenyl amides and esters), (j) carboxyl (including C₁-C₆ alkyland phenyl esters), (k) carboxy(C₂-C₅)alkoxy, (l)carboxy(C₂-C₅)alkylthioxy, (m) heterocyclylacyl, (n) heteroarylacyl, or(o) hydroxyl; (4) m′ is 0, 1, 2 or 3; (B) -E(Q)_(m″) wherein E and —Qare as defined as above and m″ is 0, 1, 2, or 3; (C) —T-E wherein -E and—Q are as defined as above; or (D) -E wherein -E is as defined as above;(III) —CO—(C₁-C₆ alkyl) where alkyl is unsubstituted or substituted withone or two: (A) —OH, (B) —C₁-C₆ alkoxy, (C) —C₁-C₆ thioalkoxy, (D)—CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or (E)—CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same or differentand are as defined above, (F) —CO—R_(N-4) where R_(N-4) is as definedabove, (G) —SO₂—(C₁-C₈ alkyl), (H) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) andR_(N-3) are the same or different and are as defined above, (I)—NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8) where R_(N-8) is as definedabove, (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above, (L) —R_(N-4) where R_(N-4) is asdefined above, (M) —O—CO—(C₁-C₆ alkyl), (N) —O—CO—NR_(N-8)R_(N-8) wherethe R_(N-8) is the same or different and are as defined above, or (O)—O—(C₁-C₅ alkyl)-COOH, (IV) —CO—(C₁-C₃ alkyl)-O—(C₁-C₃ alkyl) wherealkyl is unsubstituted or substituted with one or two (A) —OH, (B)—C₁-C₆ alkoxy, (C) —C₁-C₆ thioalkoxy, (D) —CO—O—R_(N-8) where R_(N-8) is—H, C₁-C₆ alkyl or (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) arethe same or different and are as defined above, (F) —CO—R_(N-4) whereR_(N-4) is as defined above, (G) —SO₂—(C₁-C₈ alkyl), (H)—SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same or differentand are as defined above, (I) —NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8)where R_(N-8) is as defined above, (K) —NR_(N-2)R_(N-3)where R_(N-2) andR_(N-3) are the same or different and are as defined above, (L) —R_(N-4)where R_(N-4) is as defined above, (M) —O—CO—(C₁-C₆ alkyl), (N)—O—CO—NR_(N-8) where the R_(N-8) are the same or different and are asdefined above, or (O) —O—(C₁-C₅ alkyl)-COOH, (V) —CO—(C₁-C₃alkyl)-S—(C₁-C₃ alkyl) where alkyl is unsubstituted or substituted withone or two (A) —OH, (B) —C₁-C₆ alkoxy, (C) —C₁-C₆ thioalkoxy, (D)—CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or (E)—CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same or differentand are as defined above, (F) —CO—R_(N-4) where R_(N-4) is as definedabove, (G) —SO₂—(C₁-C₈ alkyl), (H) —SO2—NR_(N-2)R_(N-3)where R_(N-2) andR_(N-3) are the same or different and are as defined above, (I)—NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8) where R_(N-8) is as definedabove, (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above, (L) —R_(N-4) where R_(N-4) is asdefined above, (M) —O—CO—(C₁-C₆ alkyl), (N) —O—CO—NRN8R_(N-8) where theR_(N-8) are the same or different and are as defined above, or (O)—O—(C₁-C₅ alkyl)-COOH, (VI)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl)) whereR_(N-aryl) and R_(N-heteroaryl) are as defined above, where R_(N-10) is:(A) —H, (B) C₁-C₆ alkyl, (C) C₃-C₇ cycloalkyl, (D) C₂-C₆ alkenyl withone double bond, (E) C₂-C₆ alkynyl with one triple bond, (F) R_(1-aryl)where R_(1-aryl) is as defined above, or (G) R_(N-heteroaryl) whereR_(N-heteroaryl) is as defined above; where B is —O—, —NH—, or —N(C₁-C₆alkyl)-; where R_(C) is: (I) —(C₁-C₁₀)alkyl-K₁₋₃ in which: (A) the alkylchain is unsubstituted or substituted with one —OH, (B) the alkyl chainis unsubstituted or substituted with one C₁-C₆ alkoxy unsubstituted orsubstituted with 1-5 —F, (C) the alkyl chain is unsubstituted orsubstituted with one —O-φ, (D) the alkyl chain is unsubstituted orsubstituted with 1-5 —F, (E) the alkyl chain is unsubstituted orsubstituted with a combination of up to three atoms of oxygen and sulfureach such atom replacing one carbon, (F) each K is: (1) H, (2) C₁-C₃alkyl, (3) C₁-C₃ alkoxy, (4) C₁-C₃ alkylthioxy, (5) C₁-C₆alkylacylamino, (6) C₁-C₆ alkylacyloxy, (7) amido (8) C₁-C₆ alkylamino(9) phenylamino, (10) carbamyl (11) carboxyl (12) carboxy(C₂-C₅)alkoxy,(13) carboxy(C₂-C₅)alkylthioxy, (14) heterocyclylacyl, (15)heteroarylacyl, (16) amino unsubstituted or substituted with C₁-C₆alkyl, (17) hydroxyl, or (18) carboxyl methyl ester;(II)-(CH₂)₀₋₃-J-[(-(CH₂)₀₋₃-K]₁₋₃ where K is as defined above and J is:(A) a 5 to 7 atom monocyclic aryl group, (B) a 8 to 12 atom multicyclicaryl group, (C) a 5 to 7 atom heterocyclic group, (D) a 8 to 12 atommulticyclic heterocyclic group, or (E) a 5 to 10 atom monocyclic ormulticyclic cycloalkyl group; (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkyl wherecycloalkyl can be unsubstituted or substituted with one, two or three(A) C_(l)-C₃ alkyl unsubstituted or substituted with 1, 2, 3, or 4 —F,—Cl, —Br, or —I, (B) —CO—OH, (C) —CO—O—(C₁-C₄ alkyl), (D) —OH, or (E)C₁-C₆ alkoxy, (IV) —(CH₂)₂-₆—OH, (V) -(CR_(C−x)R_(Cy))₀₋₄—R_(C-aryl)where R_(C−x) and R_(C−y) are —H, C₁-C₄ alkyl and and R_(C-aryl) is thesame as R_(N-aryl), (VI) —(CH₂)₀₋₄—R_(C-heteroaryl) whereR_(C-heteroaryl) is: (A) pyridinyl, (B) pyrimidinyl, (C) quinolinyl, (D)indenyl, (E) indanyl, (F) benzothiophenyl, (G) indolyl, (H) indolinyl,(I) pyridazinyl, (J) pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M)quinazolinyl, (N) quinoxalinyl, (O) phthalazinyl, (P) isoxazolyl, (Q)pyrazolyl, (R) indolizinyl, (S) indazolyl, (T) benzothiazolyl, (U)benzimidazolyl, (V) benzofuranyl, (W) furanyl, (X) thienyl, (Y)pyrrolyl, (Z) oxadiazolyl, (AA) thiadiazolyl, (BB) triazolyl, (CC)tetrazolyl, (DD) 1,4-benzodioxan (EE) purinyl, (FF) oxazolopyridinyl,(GG) imidazopyridinyl, (HH) isothiazolyl, (II) naphthyridinyl, (JJ)cinnolinyl, (KK) carbazolyl, (LL) P-carbolinyl, (MM) isochromanyl, (NN)chromanyl, (OO) furazanyl, (PP) tetrahydroisoquinoline, (QQ)isoindolinyl, (RR) isobenzotetrahydrofuranyl, (SS)isobenzotetrahydrothienyl, (TT) isobenzothiophenyl, (UU) benzoxazolyl,or (VV) pyridopyridinyl, (VII) —(CH₂)₀₋₄—R_(C-heterocycle) whereR_(C-heterocycle) is the same as R_(1-heterocycle), (VIII)—C(R_(C−1))(R_(C−2))—CO—NH—R_(C−3) where R_(C−1) and R_(C−2) are thesame or different and are: (A) —H, (B) —C₁-C₆ alkyl, (C) —(C₁-C₄alkyl)-R_(C′-aryl) where R_(C′-aryl) is as defined above for R_(1-aryl),(D) —(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is as definedabove, (E) —(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle) isas defined above, (F) —R_(C-heteroaryl) where R_(C-heteroaryl) is asdefined above, (G) —R_(C-heterocycle) where R_(C-heterocycle) is asdefined above, (H) —(CH₂)₁₋₄—OH, (I)—(CH₂)₁₋₄—R_(C−4)-(CH₂)₁₋₄—R_(C′-aryl) where R_(C−4) is —O—, —S—, —NH—or—NHR_(C−5)- where R_(C−5) is C₁-C₆ alkyl, and where R_(C′-aryl) is asdefined above, (J) —(CH₂)₁₋₄—R_(C−4)-(CH₂)₁₋₄—R_(C-heteroaryl) whereR_(C−4) and R_(C-heteroaryl) are as defined above, or (K) —R_(C′-aryl)where R_(C′-aryl) is as defined above, and where R_(C−3) is: (A) —H, (B)-C₁-C₆ alkyl, (C) —R_(C′-aryl) where R_(C′-aryl) is as defined above,(D) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above, (E)—R_(C-heterocycle) where R_(C-heterocycle) is as defined above, (F)-(C₁-C₄ alkyl)-R_(C′aryl) where R_(C′-aryl) is as defined above, (G)-(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is as definedabove, or (H) -(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle)is as defined above, (IX) —CH(φ)₂, (X) -cyclopentyl or -cyclohexyl ringfused to a phenyl or heteroaryl ring where heteroaryl is as definedabove and phenyl and heteroaryl are unsubstituted or substituted withone, two or three: (A) C₁-C₃ alkyl, (B) —CF₃, (C) —F, Cl, —Br and —I,(D) C₁-C₃ alkoxy, (E) —OCF₃, (F) —NH₂, (G) —OH, or (H) —C≡N, (XI)—CH₂—C≡CH; (XII) —(CH₂)₀₋₁-CHR_(C−5)—(CH₂)₀₋₁-φ where R_(C−5) is: (A)—OH, or (B) —CH₂—OH; (XIII) —CH(-φ)—CO—O(C₁-C₃ alkyl); (XIV)—CH(—CH₂—OH)—CH(—OH)—+—NO₂; (XV) —(CH₂)₂—O—(CH₂)₂—OH; (XVI)—CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; (XVII) —(C₂-C₈) alkynyl; or (XVIII) —H; ora pharmaceutically acceptable salt thereof.
 74. A method of treatmentaccording to claim 73 where the disease is Alzheimer's disease.
 75. Amethod of treatment according to claim 73 where the disease is Down'ssyndrome.
 76. A method of treatment according to claim 73 where thedisease is Hereditary Cerebral Hemorrhage with Amyloidosis of theDutch-Type.
 77. A method of treatment according to claim 73 where thedisease is cerebral amyloid angiopathy,
 78. A method of treatmentaccording to claim 73 where the disease is degenerative dementias.
 79. Amethod of treatment according to claim 73 where the disease is dementiaassociated with Parkinson's disease.
 80. A method of treatment accordingto claim 73 where the method is treating a disease or condition thatalready exists.
 81. A method of treatment according to claim 73 wherethe method is preventing a disease or condition from developing.
 82. Amethod of treatment according to claim 73 where the therapeuticallyeffective amount for oral administration is from about 0.1 mg/day toabout 1,000 mg/day; for parenteral, sublingual, intranasal, intrathecaladministration is from about 0.5 to about 100 mg/day; for depoadministration and implants is from about 0.5 mg/day to about 50 mg/day;for topical administration is from about 0.5 mg/day to about 200 mg/day;for rectal administration is from about 0.5 mg to about 500 mg.
 83. Amethod of treatment according to claim 73 where the therapeuticallyeffective amount is for oral administration is from about 1 mg/day toabout 100 mg/day and for parenteral administration is from about 5 toabout 50 mg daily.
 84. A method of treatment according to claim 73 wherethe therapeutically effective amount for oral administration is fromabout 5 mg/day to about 50 mg/day.
 85. A method of treatment accordingto 73 where R₁ is: (V) —(CH₂)₀₋₃-(R_(1-aryl)), or (VI)—(CH₂)_(n1)-(R_(1-heteroaryl)) where R_(N) is: (I) R_(N-1)-X_(N)- whereX_(N) is: (A) —CO3—, or (B) —SO₂—, where R_(N-1) is: (A) R_(N-aryl), or(B) —R_(N-heteroaryl), (VI)—CO—CH(—(CH₂)0-2—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl)) whereR_(C) is: (I)-C₁-C₈ alkyl, (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkyl, (IV)—(CH₂)₀₋₃—OH, (V) —(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI)—(CH₂)₀₋₄—R_(C-heteroayl,) (VII) —(CH₂)₀₋₄—R_(C-heterocyle), (VIII)—C(R_(C−1))(R_(C) ⁻²)—CO—NH—R_(C−3), or (X) -cyclopentyl or -cyclohexylring fused to a phenyl or heteroaryl ring where heteroaryl is as definedabove and phenyl and heteroaryl are unsubstituted or substituted withone or two: (A) C₁-C₃ alkyl, (B) —CF₃, (C) —F, Cl, —Br or -, (D) C₁-C₃alkoxy, or (E) —OCF₃.
 86. A method of treatment according to claim 85where R₁ is: (V) —CH₂—(R_(1-aryl)), or (VI) —CH₂—(R_(1-heteroayl));where R₂ is —H; where R_(N) is: (I) R_(N-1)—X_(N)- where X_(N) is: (A)—CO—, where R_(N-1) is: (A) R_(N-aryl), or (B) —R_(N-heteroaryl), whereR_(C) is: (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkyl, (V)—(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI) —(CH₂)₀₋₄—R_(C-heteroaryl), (VII)—(CH₂)₀₋₄—R_(C-heterocycle), (VIII) —C(R_(C−1))(R_(C−2))—CO—NH—R_(C−3),or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroarylring.
 87. A method of treatment according to claim 86 where R_(C) is:(V) —(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI) —(CH₂)₀₋₄—R_(C-heteroaryl),or (X) -cyclopentyl or -cyclohexyl ring fised to a phenyl or heteroarylring.
 88. A method of treatment according to claim 73 where R₁ is:—CH₂-(R_(1-aryl)) where R_(1-aryl) is phenyl.
 89. A method of treatmentaccording to claim 88 where R₁ is: —CH₂-(R_(1-aryl)) where R_(1-aryl) isphenyl substituted with two —F.
 90. A method of treatment according toclaim 89 where phenyl is substituted with two - F in the 3- and 5-positions giving 3,5-difluorophenyl.
 91. A method of treatment accordingto claim 73 where R₂ is: (I) —H, (II) C₁-C₆ alkyl, or (III)—(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl).
 92. A method of treatmentaccording to claim 73 where R₂ is: (II) C₁-C₆ alkyl, or (III) benzyl.93. A method of treatment according to claim 73 where R_(N) isR_(N-1)-X_(N)- where X_(N) is —CO—, where R_(N-1) is R_(N-aryl) whereR_(N-aryl) is phenyl substituted with one —CO—NR_(N-2)R_(N-3)where thesubstitution on phenyl is 1,3-.
 94. A method of treatment according toclaim 73 where R_(N-2) and R_(N-3) are the same and are C₃ alkyl.
 95. Amethod of treatment according to claim 73 where R_(N) is R_(N-1)—X_(N)—where X_(N) is —CO—, where R_(N-1) is R_(N-aryl), where R_(N-aryl) isphenyl substituted with one C₁ alkyl and with one—CO—NR_(N-2)R_(N-3)where the substitution on the phenyl is 1,3,5-.
 96. Amethod of treatment according to claim 95 where R_(N-2) and R_(N-3) arethe same and are C₃ alkyl.
 97. A method of treatment according to claim73 where R_(N) is R_(N-1)-X_(N)- where X_(N) is —CO—, where R_(N-1) isR_(N-heteroaryl) where R_(N-heteroaryl) is substituted with one—CO—NR_(N-2)R_(N-3).
 98. A method of treatment according to claim 73where R_(N-2) and R_(N-3) are the same and are -C₃ alkyl.
 99. A methodof treatment according to claim 73 where R_(N) is: A—X_(N)- where X_(N)is —CO—, where A is: (C) C₁₀H₇—CH(OH)—, or (D) t-butoxy.
 100. A methodof treatment according to claim 73 where R_(C) is: (V)—(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI) —(CH₂)₀₋₄—R_(C-heteroaryl), (VII)—(CH₂)₀₋₄—R_(C-heterocycle), (X) -cyclopentyl or -cyclohexyl ring fusedto a phenyl or heteroaryl ring where heteroaryl is as defined above andphenyl and heteroaryl are unsubstituted or substituted with one or two:(A) C₁-C₃ alkyl, (B) —CF₃, (C) —F, Cl, —Br or —I, (D) C₁-C₃ alkoxy, (E)—OCF₃, or (XVIII) —H.
 101. A method of treatment according to claim 100where R_(C) is: (V) —(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl) where R_(C-aryl) isphenyl.
 102. A method of treatment according to claim 101 where phenylsubstituted in the 3-position or 3,5-positions.
 103. A method oftreatment according to claim 100 where R_(C) is: (VI)—CH₂—R_(C-heteroaryl),
 104. A method of treatment according to claim 100where R_(C) is: (VII) —CH₂—R_(C-heterocycle).
 105. A method of treatmentaccording to claim 100 where R_(C) is: (X) -cyclohexyl ring fused to aphenyl ring.
 106. A method of treatment according to claim 73 whereR_(C) is: (I) —(C₁-C₁₀)alkyl-K¹⁻³ where each K is: (1) H, (11) carboxyl,(16) amino unsubstituted or substituted with C₁-C₆ alkyl; or (18)carboxyl methyl ester; (II) —(CH₂)₀₋₃-J-[-K]₁₋₃, where J is: (A) a 5 to7 atom monocyclic aryl group, or (B) a 5 to 10 atom multicycliccycloalkyl group, and each K is: (1) H, (3) C₁-C₃ alkoxy, or (11)carboxyl, (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkyl where cycloalkyl can beunsubstituted or substituted with one, two or three: (B) —CO—OH, (C)—CO—O—(C₁-C₄ alkyl), or (E) C₁-C₆ alkoxy, (IV) —(CH₂)₂ ₆—OH, (V)—(CH₂)₀₋₄—R_(C-aryl), (VI) —(CH₂)₀₋₄—R_(C-heteroaryl), (VII)—(CH₂)₀₋₄—R_(C-heterocycle), or (XVIII) —(C₂-C₈) alkynyl.
 107. A methodof treatment according to claim 73 where R_(C) is: (I) —(C₁-C₁₀)alkyl-Kwhere K is H, carboxyl, carboxyl methyl ester, amino unsubstituted orsubstituted with C₁-C₆ alkyl, (II) a benzyl or phenylpropyl groupsubstituted with a carboxyl group, (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkylwhere cycloalkyl is cyclohexyl, cyclohexyl substituted with 1 or 2carboxyl groups, or cyclohexyl substituted with 1 or 2 alkoxy groups,(V) —(CH₂)₀₋₄-phenyl substituted or unsubstituted with F, (VI)—(CH₂)₀₋₄-heteroaryl, or (VII) selected from -(CH₂)₀₋₄-morpholinyl and—(CH₂)₀₋₄-tetrahydrofuryl.
 108. A method of treatment according to claim73 where R_(C) is: (I) C₅H₁₀-K or C₇H₁₄-K where K is carboxyl orcarboxyl methyl ester, (II) a benzyl or phenylpropyl group substitutedwith a carboxyl group at the 5-position, or (III) a cyclohexyl ringsubstituted at the 3- and 5- positions or at the 4-position with acarboxyl group.
 109. A method of treatment according to claim 73 whereR₁ is: (I) C₁-C₅ alkyl, (II) —(CH₂)₁-₂—S—CH₃, (IV) C₁-C₅ alkenyl, (V)—(CH2)₀₋₃-(R_(1-aryl)) where R_(1-aryl) is as defined above, and (VI)—(CH₂) ₀₋₃—R_(1-heteroaryl)) where R_(1-heteroaryl) is as defined above,wherein any of the above are unsubstituted or substituted with up to twoC₁-C₃ alkyl, —F, —Cl, —Br, —I, or —CF₃; where R₂ is: (1) —H, (II) C₁-C₆alkyl, or (III) —(CH₂)₀₋₃-R₂, where R₂, is (C₃-C₆)cycloalkyl, R_(1-aryl)or R_(1-heteroaryl) where R_(1-aryl) is a 5 or 6-membered aryl group andR_(1-heteroaryl) is as defined above; where RN is: (II) A—XN—where XN is—CO—, wherein A is (A) —T-E—(Q)_(m′), (1) where —T is

where (a) x=1 when y=1 and x=2 when y=0, (b) m is 0, 1, 2 or 3, (c) thevalues of x and y vary independently on each carbon when m is 2 and 3,and (d) R′″ varies independently on each carbon and is H, (C₁-C₂) alkyl,phenyl, or phenyl(C₁-C₃)alkyl; (2) -E is (a) C₁-C₅ alkyl, but only if m′does not equal 0, (b) methylthioxy(C₂-C₄)mkyl, (c) an aryl group having5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (d) aheterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12atoms when fused, (e) a mono or fused ring cycloalkyl group having 5 to10 carbon atoms, (f) biphenyl, (g) diphenyl ether, (h) diphenylketone,(i) phenyl(C₁-C₈)alkyloxyphenyl, or (j) C₁-C₆ alkoxy; (3) —Q is (a)C₁-C₃ alkyl, (b) C₁-C₃ alkoxy, (c) C₁-C₃ alkylthioxy, (d) C₁-C₆alkylacylamino, (e) C₁-C₆ alkylacyloxy, (f) amido (including primary,C₁-C₆ alkyl and phenyl secondary and tertiary amino moieties), (g) C₁-C₆alkylamino (h) phenylamino, (i) carbamyl (including C₁-C₆ alkyl andphenyl amides and esters), (j) carboxyl (including C₁-C₆ alkyl andphenyl esters), (k) carboxy(C₂-C₅)alkoxy, (l) carboxy(C₂-C₅)alkylthioxy,(m) heterocyclylacyl, (n) heteroarylacyl, or (o) hydroxyl; (4) m′ is 0,1, 2 or 3; (B) -E(Q)_(m″) wherein E and —Q are as defined as above andm″ is 0, 1, 2, or 3; (C) —T-E wherein -E and —Q are as defined as above;or (D) -E wherein -E is as defined as above; where R_(C) is: (I)—(C₁-C₁₀)alkyl-K₁₋₃ (E) the alkyl chain optionally contains acombination of up to three atoms of oxygen and sulfur each such atomreplacing one carbon, (F) each K is: (2) C₁-C₃ alkyl, (3) C₁-C₃ alkoxy,(4) C₁-C₃ alkylthioxy, (5) C₁-C₆ alkylacylamino, (6) C₁-C₆ alkylacyloxy,(7) amido, (8) C₁-C₆ alkylamino (9) phenylamino, (10) carbamyl (11)carboxyl, (12) carboxy(C₂-C₅)alkoxy, (13) carboxy(C₂-C₅)alkylthioxy,(14) heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted orsubstituted with C₁-C₆ alkyl, (17) hydroxyl, or (18) carboxyl methylester; (II) —(CH₂)₀₋₃-J-[(—(CH₂)₀₋₃-K]₁₋₃ where K is: (2) C₁-C₃ alkyl,(3) C₁-C₃ alkoxy, (4) C₁-C₃ alkylthioxy, (5) C₁-C₆ alkylacylamino, (6)C₁-C₆ alkylacyloxy, (7) amido, (8) C₁-C₆ alkylamino (9) phenylamino,(10) carbamyl, (11) carboxyl, (12) carboxy(C₂-C₅)alkoxy, (13)carboxy(C₂-C₅)alkylthioxy, (14) heterocyclylacyl, (15) heteroarylacyl,(16) amino unsubstituted or substituted with C_(l)-C₆ alkyl, (17)hydroxyl, or (18) carboxyl methyl ester; J is: (A) a 5 to 7 atommonocyclic aryl group, (B) a 8 to 12 atom multicyclic aryl group, (C) a5 to 7 atom monocyclic heterocyclic group, (D) a 8 to 12 atommulticyclic heterocyclic group, or (E) a 5 to 10 atom monocyclic ormulticyclic cycloalkyl group; and where B is O or NH.
 110. A method oftreatment according to claim 73 where the pharmaceutically acceptablesalt is a salt of hydrochloric, hydrobromic, hydroiodic, nitric,sulfuric, phosphoric, citric, methanesulfonic, CH₃—(CH₂),—COOH where nis 0 thru 4, HOOC—(CH₂)n—COOH where n is as defined above,HOOC—CH═CH—COOH and φ—COOH acid or triethanolamine, N-methylglucamine,diethanolamine, ethanolamine, tris(hydroxymethyl)aminomethane (TRIS),amnmonia, or carbonate, bicarbonate, phosphonate, or hydroxide salts ofan alkali or alkaline earth metal.
 111. A method of treatment accordingto claim 73 wherein said compound is: N-[(1S, 2S,4R)-1-(3,5-Difluorobenzyl)-4-(syn,syn)-(3,5-dimethoxycyelohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide,6-[6-(3,5-Difluorophenyl)-5-(5)-(3-dipropylarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoicacid,5-[6-(3,5-Difluorophenyl)-5-(5)-(3-dipropylarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-pentanoicacid,4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyricacid,3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionicacid,8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoicacid,8-[6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoicacid methyl ester,N-[4-(R)-Butylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide,N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamnide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide,4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethy₁₋₄-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid methyl ester,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(5)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid methyl ester,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(s)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(5)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,orN-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide.112. A method of treatment according to claim 73 wherein said compoundis:


113. A pharmaceutical composition which comprises a compound of formula

where R₁ is: (I) C₁-C₆ alkyl, unsubstituted or substituted with one, twoor three C₁-C₃ alkyl, —F, —Cl, —Br, —I, —OH, —NH_(2,) —C—N, —CF₃, or—N₃, (II) —(CH₂)₁₋₂—S—CH₃, (III) —CH₂—CH₂—S—CH₃, (IV) —CH₂—(C₂-C₆alkenyl) unsubstituted or substituted by one —F, (V)—(CH₂)₀₋₃-(R_(1-aryl)) where R_(1-aryl) is phenyl, 1-naphthyl,2-naphthyl, indanyl, indenyl, dihydronaphthyl, tetralinyl unsubstitutedor substituted on the aryl ring with one or two of the followingsubstituents which can be the same or different: (A) C₁-C₃ alkyl, (B)—CF₃, (C) —F, Cl, —Br and —I, (D) C₁-C₃ alkoxy, (E) —O—CF₃, (F) —NH₂,(G) —OH, or (H) —C≡N, (VI) —(CH₂)_(n1)-(R_(1-heteroaryl)) where n, is 0,1, 2, or 3 and R_(1-heteroaryl) is: (A) pyridinyl, (B) pyrimidinyl, (C)quinolinyl, (D) indenyl, (E) indanyl, (F) benzothiophenyl, (G) indolyl,(H) indolinyl, (I) pyridazinyl, (J) pyrazinyl, (K) isoindolyl, (L)isoquinolyl, (M) quinazolinyl, (N) quinoxalinyl, (O) phthalazinyl, (P)imidazolyl, (Q) isoxazolyl, (R) pyrazolyl, (S) oxazolyl, (T) thiazolyl,(U) indolizinyl, (V) indazolyl, (W) benzothiazolyl, (X) benzimidazolyl,(Y) benzoffiranyl, (Z) furanyl, (AA) thienyl, (BB) pyrrolyl, (CC)oxadiazolyl, (DD) thiadiazolyl, (EE) triazolyl, (FF) tetrazolyl, (GG)1,4-benzodioxan (HH) purinyl, (II) oxazolopyridinyl, (JJ)imidazopyridinyl, (KK) isothiazolyl, (LL) naphthyridinyl, (MM)cinnolinyl, (NN) carbazolyl, (OO) β-carbolinyl, (PP) isochromanyl, (QQ)chromanyl, (RR) furazanyl, (SS) tetrahydroisoquinoline, (TT)isoindolinyl, (UU) isobenzotetrahydrofuranyl, (VV)isobenzotetrahydrothienyl, (WW) isobenzothiophenyl, (XX) benzoxazolyl,or (YY) pyridopyridinyl, where the R_(1 heteroaryl) group is bonded to—(CH₂)₀₋₃— by any ring atom of the parent R_(N-heteroaryl) groupsubstituted by hydrogen such that the new bond to the R_(1-heteroaryl)group replaces the hydrogen atom and its bond, where heteroaryl isunsubstituted or substituted with one or two: (1) C₁-C₃ alkyl, (2) —CF₃,(3) —F, Cl, —Br, or —I, (4) C₁-C₃ alkoxy, (5) —O—CF₃, (6) —NH₂, (7) —OH,or (8) —C≡N, with the proviso that when n₁ is zero R_(1-heteroaryl) isnot bonded to the carbon chain by nitrogen, or (VII)—(CH₂)_(n1)-(R_(1-heterocycle)) where n₁ is as defined above andR_(1-heterocycle) is: (A) morpholinyl, (B) thiomorpholinyl, (C)thiomorpholinyl S-oxide, (D) thiomorpholinyl S,S-dioxide, (E)piperazinyl, (F) homopiperazinyl, (G) pyrrolidinyl, (H) pyrrolinyl, (I)tetrahydropyranyl, (J) piperidinyl, (K) tetrahydrofuranyl, or (L)tetrahydrothiophenyl, where the R_(1-heterocycle) group is bonded by anyatom of the parent R_(1-heterocycle) group substituted by hydrogen suchthat the new bond to the R_(1-heteroaryl) group replaces the hydrogenatom and its bond, where heterocycle is unsubstituted or substitutedwith one or two: (1) ═O, (2) C₁-C₃ alkyl, (3) —CF₃, (4) —F, Cl, —Br and—I, (5) C₁-C₃ alkoxy, (6) —0—CF₃, (7) —NH₂, (8) —OH, or (9) —CN, withthe proviso that when n₁ is zero RI heterocycle is not bonded to thecarbon chain by nitrogen; where R₂ is: (I) —H, (II) C₁-C₆ alkyl, or(III) —(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is (C₃-C₆)cycloalkyl, R_(1-aryl) orR_(1-heteroaryl) where R_(1-aryl) and R_(1-heteroaryl) are as definedabove, where R_(N) is: (I) R_(N-1), X_(N)- where X_(N) is: (A) —CO—, (B)—SO₂—, (C) —(CR′R″)₁₋₆ where R′ and R″ are the same or different and are—H or C₁-C₄ alkyl, (D) —CO—(CR′RΔ)₁₋₆-X_(N-1) where X_(N-1) is —O—,—S—and —NR′R″- and where R′ and R″ are as defined above, (E) a singlebond; where R_(N-1) is: (A) R_(N-aryl) where R_(N-aryl) is phenyl,1-naphthyl and 2-naphthyl unsubstituted or substituted with one, two,three or four of the following substituents which can be the same ordifferent and are: (1) C₁-C₆ alkyl, (2) —F, —Cl, —Br, or —I, (3)—OH, (4)—NO₂, (5) —CO—OH, (6) —CN, (7) —CO—NR_(N-2)R_(N-3)where R_(N-2) andR_(N-3) are the same or different and are: (a) —H, (b) —C₁-C₆ alkylunsubstituted or substituted with one (i) —OH, or (ii) —NH₂, (c) —C₁-C₆alkyl unsubstituted or substituted with one to three —F, —Cl, —Br, or—I, (d) —C₃-C₇ cycloalkyl, (e) —(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), (f)—(C₁-C₆ alkyl)-O—(C₁-C₃ alkyl), (g) —C₁-C₆ alkenyl with one or twodouble bonds, (h) —C₁-C₆ alkynyl with one or two triple bonds, (i)—C₁-C₆ alkyl chain with one double bond and one triple bond, (j)—R_(1-aryl) where R_(1-aryl) is as defined above, or (k)—R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (8)—CO—(C₃-C₁₂ alkyl), (9) —CO—(C₃-C₆ cycloalkyl), (10) —CO—R -heteroarylwhere R_(1-heteroaryl) is as defined above, (11) —CO—R_(1-heterocycle)where R_(1-heterocycle) is as defined above, (12) —CO—R_(N-4) whereR_(N-4) is morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl orpyrrolidinyl where each group is unsubstituted or substituted with oneor two C₁-C₃ alkyl, (13) —CO—O—R_(N-5) where R_(N-5) is: (a) C₁-C₆alkyl, or (b) —(CH₂)₀₋₂-(R_(1-aryl)) where R_(1-aryl) is as definedabove, (14) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are as definedabove, (15) —SO—(C₁-C₈ alkyl), (16) —SO₂(C₃-C₁₂ alkyl), (17)—NH—CO—O—RN₅ where R_(N-5) is as defined above, (18) —NH—CO—N(C₁-C₃alkyl)₂, (19) —N—CS—N(C₁-C₃ alkyl)₂, (20) —N(C₁-C₃ alkyl)-CO—R_(N-5)where R_(N-5) is as defined above, (21) —NR_(N-2)R_(N-3)where R_(N-2)and R_(N-3) can be the same or different and are as defined above, (22)—R_(N-4) where R_(N-4) is as defined above, (23) —O—CO—(C₁-C₆ alkyl),(24) —O—CO—N(C₁-C₃ alkyl)₂, (25) —O—CS—N(C₁-C₃ alkyl)₂, (26) —O—(C₁-C₆alkyl), (27) —O—(C₂-C₅ alkyl)-COOH, (28) —S—(C₁-C₆ alkyl), (29) C₁-C₆alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —F, (30)—O—(C₁-C₆ alkyl unsubstituted or substituted with 1, 2, 3, 4, or 5 —F,or (31) —O-φ, (B) R_(N-heteroaryl) where R_(N-heteroaryl) is: (A)pyridinyl, (B) pyrimidinyl, (C) quinolinyl, (D) indenyl, (E) indanyl,(F) benzothiophenyl, (G) indolyl, (H) indolinyl, (I) pyridazinyl, (J)pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M) quinazolinyl, (N)quinoxalinyl, (O) phthalazinyl, (P) imidazolyl, (Q) isoxazolyl, (R)pyrazolyl, (S) oxazolyl, (T) thiazolyl, (U) indolizinyl, (V) indazolyl,(W) benzothiazolyl, (X) benzimidazolyl, (Y) benzofuranyl, (Z) furanyl,(AA) thienyl, (BB) pyrrolyl, (CC) oxadiazolyl, (DD) thiadiazolyl, (EE)triazolyl, (FF) tetrazolyl, (GG) 1,4-benzodioxan (HH) purinyl, (II)oxazolopyridinyl, (JJ) imidazopyridinyl, (KK) isothiazolyl, (LL)naphthyridinyl, (MM) cirnolinyl, (NN) carbazolyl, (OO) β-carbolinyl,(PP) isochromanyl, (QQ) chromanyl, (RR) furazanyl, (SS)tetrahydroisoquinoline, (TT) isoindolinyl, (UU)isobenzotetrahydrofuranyl, (VV) isobenzotetrahydrothienyl, (WW)isobenzothiophenyl, (XX) benzoxazolyl, or (YY) pyridopyridinyl, wherethe R_(N-heteroaryl) group is bonded by any atom of the parentR_(N-heteroaryl) group substituted by hydrogen such that the new bond tothe R_(N-heteroaryl) group replaces the hydrogen atom and its bond,where heteroaryl is unsubstituted or substituted with one or two: (1)C₁-C₆ alkyl, (2)—F, —Cl, —Br, or —I, (3) —OH, (4) —NO₂, (5) —CO—OH, (6)—C≡N, (7) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are: (a) —H, (b) —C₁-C₆ alkyl unsubstituted or substitutedwith one (i) —OH, or (ii) —NH₂, (c) —C₁-C₆ alkyl unsubstituted orsubstituted with 1, 2, or 3 —F, —Cl, —Br, or —I, (d) —C₃-C₇ cycloalkyl,(e) -(C₁-C₂ alkyl)-(C₃-C₇ cycloalkyl), (f) —(C₁-C₆ alkyl)-O—(C₁-C₃alkyl), (g) —C₁-C₆ alkenyl with one or two double bonds, (h) —C₁-C₆alkynyl with one or two triple bonds, (i) —C₁-C₆ alkyl chain with onedouble bond and one triple bond, (j) —R_(1-aryl) where R_(1-aryl) is asdefined above, or (k) —R_(1-heteroaryl) where R_(1-heteroaryl) is asdefined above, (8) —CO—(C₃-C₁₂ alkyl), (9) —CO—(C₃-C₆ cycloalkyl), (10)CO-R_(1-heteroaryl) where R_(1-heteroaryl) is as defined above, (11)—CO—R_(1-heterocycle) where R_(1-heterocycle) is as defined above, (12)—CO—R_(N-4) where R_(N-4) is morpholinyl, thiomorpholinyl, piperazinyl,piperidinyl or pyrrolidinyl where each group is unsubstituted orsubstituted with one or two C₁-C₃ alkyl, (13) —CO—O—R_(N-5) whereR_(N-5) is: (a) C₁—C₆ alkyl, or (b) —(CH₂)₀₋₂-(R_(1-aryl)) whereR_(1-aryl) is as defined above, (14) —SO₂—NR_(N-2)R_(N-3) where R_(N-2)and R_(N-3) are as defined above, (15) —SO—(C₁-C₈ alkyl), (16)—SO₂(C₃-C₁₂ alkyl), (17) —NH—CO—O—R_(N-5) where R_(N-5) is as definedabove, (18) —NH—CO—N(C₁-C₃ alkyl)₂, (19) —N—CS—N(C₁-C₃ alkyl)₂, (20)—N(C₁-C₃ alkyl)-CO—R_(N-5) where R_(N-5) is as defined above, (21)—NR_(N-2)R_(N-3) where R_(N-2) and R_(N-3) can be the same or differentand are as defined above, (22) —R_(N-4) where R_(N-4) is as definedabove, (23) —O—CO—(C₁-C₆ alkyl), (24) —O—CO—N(C₁-C₃ alkyl)₂, (25)—O—CS—N(C₁-C₃ alkyl)₂, (26) —O—(C₁-C₆ alkyl), (27) —O—(C₂-C₅alkyl)-COOH, or (28) —S—(C₁-C₆ alkyl), (C) —R_(N-aryl)—R_(N-aryl) where—R_(N-aryl) is as defined above, (D) —R_(N-aryl)—R_(N-heteroaryl) where—R_(N-aryl) and R_(N-heteroaryl) are as defined above, (E)—R_(N-heteroaryl)—R_(N-aryl) where —R_(N-aryl) and —R_(N-heteroaryl) areas defined above, (F) —R_(N-heteroaryl)—R_(N-heteroaryl) whereR_(N-heterorayl) is as defined above, (G) —R_(N-aryl)-O—R_(N-aryl),where —R_(N-aryl) is as defined above, (H) —R_(N-aryl)—S—R_(N-aryl)where —R_(N-aryl) is as defined above, (I)—R_(N-heteroaryl)-O—R_(N-heteroaryl) where R_(N-heteraryl) is as definedabove, (J) —R_(N-heteroaryl)—S—R_(N-heteroaryl) where R_(N-heteroaryl)is as defined above, (K) —R_(N-aryl)—CO—R_(N-aryl) where —R_(N-aryl) isas defined above, (L) —R_(N-aryl)—CO—R_(N-heteroaryl) where —R_(N-aryl)and R_(N-heteroaryl are as defined above,) (M) —R_(N-aryl)—SO₂R_(N-aryl)where —R_(N-aryl) is as defined above, (N)—R_(N-heteroaryl)—CO—R_(N-heteroaryl) where R_(N-heteroaryl) is asdefined above, (O) —R_(N-heteroaryl)—SO₂—R_(N-heteroaryl) whereR_(N-heteroaryl) is as defined above, (P) —R_(N-aryl)-O—(C₁-C₈ alkyl)-φ)where R_(N-aryl) is as defined above, (Q) —R_(N-aryl)—S—(C₁-C₈ alkyl)-where R_(N-aryl) is as defined above, (R) —R_(N-heteroaryl)-O—(C₁-C₈alkyl)-φ where R_(N-heteroaryl) is as defined above,or (S)—R_(N-heteroaryl)—S—(C₁-C₈ alkyl)-φ where R_(N-heteroaryl) is as definedabove, (II) () A—X_(N)- where X_(N) is —CO—, wherein A is (A)—T-E—(Q)_(m′), (1) where —T is

where (a) x=1 when y=1 and x=2 when y=0, (b) m is 0, 1, 2 or 3, (c) thevalues of x and y vary independently on each carbon when m is 2 and 3,and (d) R′″ varies independently on each carbon and is H, (C₁-C₂) alkyl,phenyl, or phenyl(C₁-C₃)alkyl; (2) -E is (a) C₁-C₅ alkyl, but only if m′does not equal 0, (b) methylthioxy(C₂-C₄)alkyl, (c) an aryl group having5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (d) aheterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12atoms when fused, (e) a mono or fused ring cycloalkyl group having 5 to10 carbon atoms, (f) biphenyl, (g) diphenyl ether, (h) diphenylketone,(i) phenyl(C₁-C₈)alkyloxyphenyl, or (j) C₁-C₆ alkoxy; (3) —Q is (a)C₁-C₃ alkyl, (b) C₁-C₃ alkoxy, (c) C₁-C₃ alkylthioxy, (d) C₁-C₆alkylacylamino, (e) C₁-C₆ alkylacyloxy, (f) amido (including primary,C₁-C₆ alkyl and phenyl secondary and tertiary amino moieties), (g) C₁-C₆alkylamino (h) phenylamino, (i) carbamyl (including C₁-C₆ alkyl andphenyl amides and esters), (j) carboxyl (including C₁-C₆ alkyl andphenyl esters), (k) carboxy(C₂-C₅)alkoxy, (l) carboxy(C₂-C₅)alkylthioxy,(m) heterocyclylacyl, (n) heteroarylacyl, or (o) hydroxyl; (4) m′ is 0,1, 2 or 3; (B) -E(Q)_(m″) wherein E and —Q are as defined as above andm″ is 0 1, 2, or 3; (C) —T-E wherein -E and —Q are as defined as above;or (D) -E wherein -E is as defined as above; (III) —CO—(C₁-C₆ alkyl)where alkyl is unsubstituted or substituted with one or two: (A) —OH,(B) —C₁-C₆ alkoxy, (C) —C₁-C₆ thioalkoxy, (D) —CO—O—R_(N-8) whereR_(N-8) is —H, C₁-C₆ alkyl or φ, (E) —CO—NR_(N-2) R_(N-3)where R_(N-2)and R_(N-3) are the same or different and are as defined above, (F)—CO—R_(N-4) where R_(N-4) is as defined above, (G) —SO₂—(C₁-C₈ alkyl),(H) —SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above, (I) —NH—CO—(C₁-C₆ alkyl), (J)—NH—CO—O—R_(N-8) where R_(N-8) is as defined above, (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same or different and are as definedabove, (L) —R_(N-4) where R_(N-4) is as defined above, (M) —O—CO—(C₁-C₆alkyl), (N) —O—CO—NR_(N-8)R_(N-8) where the R_(N-8) is the same ordifferent and are as defined above, or (O) —O—(C₁-C₅ alkyl)-COOH, (IV)—CO—(C₁-C₃ alkyl)-O—(C₁-C₃ alkyl) where alkyl is unsubstituted orsubstituted with one or two (A) —OH, (B) —C₁-C₆ alkoxy, (C) —C₁-C₆thioalkoxy, (D) —CO—O—R_(N-8) where R_(N-8) is —H, C₁-C₆ alkyl or -φ,(E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same ordifferent and are as defined above, (F) —CO—R_(N-4) where R_(N-4) is asdefined above, (G) —SO₂—(C₁-C₈ alkyl), (H) —SO₂—NR_(N-2)R_(N-3)whereR_(N-2) and R_(N-3) are the same or different and are as defined above,(I) —NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8) where R_(N-8) is asdefined above, (K) —NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are thesame or different and are as defined above, (L) —R_(N-4) where R_(N-4)is as defined above, (M) —O—CO—(C₁-C₆ alkyl), (N) —O—CO—NR_(N-8)R_(N-8)where the R_(N-8) are the same or different and are as defined above, or(O) —O—(C₁-C₅ alkyl)-COOH, (V) —CO—(C₁-C₃ alkyl)-S—(C₁-C₃ alkyl) wherealkyl is unsubstituted or substituted with one or two (A) —OH, (B)-C₁-C₆ alkoxy, (C) —C₁-C₆ thioalkoxy, (D) —CO—O—R_(N-8) where R_(N-8) is—H, C₁-C₆ alkyl or (E) —CO—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) arethe same or different and are as defined above, (F) —CO—R_(N-4) whereR_(N-4) is as defined above, (G) —SO₂—(C₁-C₈ alkyl), (H)—SO₂—NR_(N-2)R_(N-3)where R_(N-2) and R_(N-3) are the same or differentand are as defined above, (I) —NH—CO—(C₁-C₆ alkyl), (J) —NH—CO—O—R_(N-8)where R_(N-8) is as defined above, (K) —NR_(N-2)R_(N-3)where R_(N-2) andR_(N-3) are the same or different and are as defined above, (L) —R_(N-4)where R_(N-4) is as defined above, (M) —O—CO—(C₁-C₆ alkyl), (N)—O—CO—NR_(N-8)R_(N-8) where the R_(N-8) are the sarne or different andare as defined above, or (O) —O—(C₁-C₅ alkyl)-COOH, (VI)—CO—CH(—(CH₂)₀₋₂—O—R_(N-10))—(CH₂)₀₋₂—R_(N-aryl)/R_(N-heteroaryl)) whereR_(N-aryl) and R_(N-heteroaryl) are as defined above, where R_(N-−1O)is: (A) —H, (B) C₁-C₆ alkyl, (C) C₃-C₇ cycloalkyl, (D) C₂-C₆ alkenylwith one double bond, (E) C₂-C₆ alkynyl with one triple bond, (F)R_(1-aryl) where R_(1-aryl) is as defined above, or (G) R_(N-heteroaryl)where R_(N-heteroaryl) is as defined above; where B is —O—, —NH—, or—N(C₁-C₆ alkyl)-; where R_(C) is: (I) —(C₁-C₁₀)alkyl-K₁₋₃ in which: (A)the alkyl chain is unsubstituted or substituted with one —OH, (B) thealkyl chain is unsubstituted or substituted with one C₁-C₆ alkoxyunsubstituted or substituted with 1-5 —F, (C) the alkyl chain isunsubstituted or substituted with one —O-φ, (D) the alkyl chain isunsubstituted or substituted with 1-5 —F, (E) the alkyl chain isunsubstituted or substituted with a combination of up to three atoms ofoxygen and sulfur each such atom replacing one carbon, (F) each K is:(1) H, (2) C₁-C₃ alkyl, (3) C₁-C₃ alkoxy, (4) C₁-C₃ alkylthioxy, (5)C₁-C₆ alkylacylamino, (6) C₁-C₆ alkylacyloxy, (7) amido (8) C₁-C₆alkylamino (9) phenylamino, (10) carbamyl (11) carboxyl (12)carboxy(C₂-C₅)alkoxy, (13) carboxy(C₂-C₅)alkylthioxy, (14)heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted orsubstituted with C₁-C₆ alkyl, (17) hydroxyl, or (18) earboxyl methylester; (II)—(CH₂)₀₋₃-J-[(—(CH₂)₀₋₃-K]₁₋₃ where K is as defined above andJ is: (A) a 5 to 7 atom monocyclic aryl group, (B) a 8 to 12 atommulticyclic aryl group, (C) a 5 to 7 atom heterocyclic group, (D) a 8 to12 atom multicyclic heterocyclic group, or (E) a 5 to 10 atom monocyclicor multicyclic cycloalkyl group; (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkylwhere cycloalkyl can be unsubstituted or substituted with one, two orthree (A) C₁-C₃ alkyl unsubstituted or substituted with 1, 2, 3, or 4—F, —Cl, —Br, or —I, (B) —CO—OH, (C) —CO—O—(C₁-C₄ alkyl), (D) —OH, or(E) C₁-C₆ alkoxy, (IV)—(CH₂)₂-₆—OH, (V) -(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl)where R_(C−x) and R_(C−y) are —H, C₁-C₄ alkyl and and R_(C-aryl) is thesame as R_(N-aryl), (VI) —(CH₂)₀₋₄—R_(C-heteroaryl) whereR_(C-heteroaryl) is: (A) pyridinyl, (B) pyrimidinyl, (C) quinolinyl, (D)indenyl, (E) indanyl, (F) benzothiophenyl, (G) indolyl, (H) indolinyl,(I) pyridazinyl, (J) pyrazinyl, (K) isoindolyl, (L) isoquinolyl, (M)quinazolinyl, (N) quinoxalinyl, (O) phthalazinyl, (P) isoxazolyl, (Q)pyrazolyl, (R) indolizinyl, (S) indazolyl, (T) benzothiazolyl, (U)benzimidazolyl, (V) benzofuranyl, (W) furanyl, (X) thienyl, (Y)pyrrolyl, (Z) oxadiazolyl, (AA) thiadiazolyl, (BB) triazolyl, (CC)tetrazolyl, (DD) 1,4-benzodioxan (EE) purinyl, (FF) oxazolopyridinyl,(GG) imidazopyridinyl, (HH) isothiazolyl, (II) naphthyridinyl, (JJ)cinnolinyl, (KK) carbazolyl, (LL) β-carbolinyl, (MM) isochromanyl, (NN)chromanyl, (OO) furazanyl, (PP) tetrahydroisoquinoline, (QQ)isoindolinyl, (RR) isobenzotetrahydrofuranyl, (SS)isobenzotetrahydrothienyl, (TT) isobenzothiophenyl, (UU) benzoxazolyl,or (VV) pyridopyridinyl, (VII ) (CH₂)₀₋₄—R_(C-heterocycle) whereR_(C-heterocycle) is the same as R_(1-heterocycle,) (VIII)—C(R_(C−1))(R_(C−2))—CO—NH—R_(C−3) where R_(C−1) and R_(C−2) are thesame or different and are: (A) —H, (B) —C₁-C₆ alkyl, (C) —(C₁-C₄alkyl)-R_(C′aryl) where R_(C′-aryl) is as defined above for R_(1-aryl),(D) —(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is as definedabove, (E) —(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle) isas defined above, (F) —R_(C-heteroaryl) where R_(C-heteroaryl) is asdefined above, (G) —R_(C-heterocycle) where R_(C-heterocycle) is asdefined above, (H) —(CH₂)₁₋₄—OH, (I) —(CH₂)₁₋₄—R_(C−4)(CH₂)₁₋₄—R_(C′-aryl) where R_(C−4) is —O—, —S—, —NH— or—NHR_(C−5)- where R_(C−5) is C₁-C₆ alkyl, and where R_(C′-aryl) is asdefined above, (J) -(CH₂)₁₋₄—R_(C−4)—(CH₂)₁₋₄—R_(C-heteroaryl) whereRC-4 and R_(C-heteroaryl) are as defined above, or (K) —R_(C′-aryl)where R_(C′-aryl) is as defined above, and where R_(C−3) is: (A) —H, (B)—C₁-C₆ alkyl, (C) —R_(C′-aryl) where R_(C′-aryl) is as defined above,(D) —R_(C-heteroaryl) where R_(C-heteroaryl) is as defined above, (E)—R_(C-heterocycle) where R_(C-heterocycle) is as defined above, (F)-(C₁-C₄ alkyl)-R_(C′aryl) where R_(C′-aryl) is as defined above, (G)-(C₁-C₄ alkyl)-R_(C-heteroaryl) where R_(C-heteroaryl) is as definedabove, or (H) —(C₁-C₄ alkyl)-R_(C-heterocycle) where R_(C-heterocycle)is as defined above, (IX) —CH(φ)₂, (X) -cyclopentyl or -cyclohexyl ringfused to a phenyl or heteroaryl ring where heteroaryl is as definedabove and phenyl and heteroaryl are unsubstituted or substituted withone, two or three: (A) C₁-C₃ alkyl, (B) —CF₃, (C) —F, Cl, —Br and —I,(D) C₁-C₃ alkoxy, (E) —OCF₃, (F) —NH₂, (G) —OH, or (H) —CN, (XI)—CH₂-C≡CH; (XII) —(CH₂)₀₋₁—CHR_(C−5)—(CH₂)₀₋₁-φ where R_(C−5) is: (A)—OH, or (B)—CH₂—OH; (XIII) —CH(-φ)—CO—O(C₁-C₃ alkyl); (XIV)—CH(—CH₂—OH)—CH(—OH)-φ—NO₂; (XV) —(CH₂)₂—O—(CH₂)₂—OH; (XVI)—CH₂—NH—CH₂—CH(—O—CH₂—CH₃)₂; (XVII) —(C₂-C₈) alkynyl; or (XVIII) —H; ora pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable inert carriers.
 114. The pharmaceuticalcomposition of claim 113 where R₁ is: (V) —(CH₂)₀₋₃-(R_(1-aryl)), or(VI) —(CH₂)_(n1)-(R_(1-heteroaryl)) where R_(N) is: (I) R_(N-1) X_(N)-where X_(N) is: (A) —CO—, or (B) —SO₂—, where R_(N-1) is: (A)R_(N-aryl), or (B) —R_(N-heteroaryl), (VI)—CO—CH(—(CH₂)0-2—O—R_(N-10))—(CH₂)0-2—R_(N-aryl)/R_(N-heteroaryl)) whereR_(C) is: (I)-C₁-C₈ alkyl, (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkyl, (IV)—(CH₂)₀₋₃—OH, (V) —(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI)—(CH₂)₀₋₄—R_(C-heteroaryl), (VII) —(CH₂)0-4—R_(C-heterocycle), (VIII)—C(R_(C−1))(R_(C−2))—CO—NH—R_(C−3), or (X) -cyclopentyl or -cyclohexylring fused to a phenyl or heteroaryl ring where heteroaryl is as definedabove and phenyl and heteroaryl are unsubstituted or substituted withone or two: (A) C₁-C₃ alkyl, (B) —CF₃, (C) —F, Cl, —Br or —I, (D) C₁-C₃alkoxy, or (E) —OCF₃.
 115. The pharmaceutical composition of claim 113where R₁ is: (V) —CH₂—(R_(1-aryl)), or (VI) —CH₂—(R_(1-heteroaryl));where R₂ is —H; where R_(N) is: (I) R_(N-1)-X_(N)- where X_(N) is: (A)—CO—, where R_(N-1) is: (A) R_(N-aryl) or (B) —R_(N-heteroaryl), whereR_(C) is: (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkyl, (V)—(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI) —(CH₂)₀₋₄R_(C-heteroaryl), (VII)—(CH₂)₀₋₄—R_(C-heterocycle), (VIII) —C(R_(C−1))(R_(C−2))—CO—NH—R_(C−3),or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroarylring.
 116. The pharmaceutical composition of claim 113 where R_(C) is:(V) -(CR_(C−x)R_(C−y))0-4—R_(C-aryl), (VI) —(CH₂)₀₋₄-P_(C-heteroaryl),or (X) -cyclopentyl or -cyclohexyl ring fused to a phenyl or heteroarylring.
 117. The pharmaceutical composition of claim 113 where R₁ is:—CH₂-(R_(1-aryl)) where R_(1-aryl) is phenyl.
 118. The pharmaceuticalcomposition of claim 113 where R₁ is: —CH₂-(R_(1-aryl)) where R_(1-aryl)is phenyl substituted with two —F.
 119. The pharmaceutical compositionof claim 113 where phenyl is substituted with two —F in the 3- and 5-positions giving 3,5-difluorophenyl.
 120. The pharmaceutical compositionof claim 113 where R₂ is: (I) —H, (II) C₁-C₆ alkyl, or (III)—(CH₂)₀₋₄—R₂₋₁ where R₂₋₁ is R_(1-aryl).
 121. The pharmaceuticalcomposition of claim 113 where R₂ is: (II) C₁-C₆ alkyl, or (III) benzyl.122. The pharmaceutical composition of claim 113 where R_(N) isR_(N-1)—X_(N)— where X_(N) is —CO—, where R_(N-1) is R_(N-aryl) whereR_(N-aryl), is phenyl substituted with one —CO—NR_(N-2) R_(N-3) wherethe substitution on phenyl is 1,3-.
 123. The pharmaceutical compositionof claim 113 where R_(N-2) and R_(N-3) are the same and are C₃ alkyl.124. The pharmaceutical composition of claim 113 where R_(N) isR_(N-1)—X_(N)— where X_(N) is —CO—, where R_(N-1) is R_(N-aryl), whereR_(N-aryl), is phenyl substituted with one C₁ alkyl and with one—CO—NR_(N-2)R_(N-3)where the substitution on the phenyl is 1,3,5-. 125.The pharmaceutical composition of claim 113 where R_(N-2) and R_(N-3)are the same and are C₃ alkyl.
 126. The pharmaceutical composition ofclaim 113 where R_(N) is R_(N-1)X_(N)- where X_(N) is —CO—, whereR_(N-1) is R_(N-heteroaryl) where R_(N-heteroaryl) is substituted withone —CO—NR_(N-2) R_(N-3).
 127. The pharmaceutical composition of claim113 where R_(N-2) and R_(N-3) are the same and are —C₃ alkyl.
 128. Thepharmaceutical composition of claim 113 where R_(N) is: A—X_(N)— whereX_(N) is —CO—, where A is: (C) C₁₀H₇—CH(OH)—, or (D) t-butoxy.
 129. Thepharmaceutical composition of claim 113 where R_(C) is: (V)—(C_(C−x)R_(C−y))₀₋₄—R_(C-aryl), (VI) —(CH₂)₀₋₄—R_(C-heteroaryl,) (VII)—(CH₂)₀₋₄—R_(C-heterocycle), (X) -cyclopentyl or -cyclohexyl ring fusedto a phenyl or heteroaryl ring where heteroaryl is as defined above andphenyl and heteroaryl are unsubstituted or substituted with one or two:(A) C₁-C₃ alkyl, (B) —CF₃, (C) —F, Cl, —Br or —I, (D) C₁-C₃ alkoxy, (E)—OCF₃, or (XVIII) —H.
 130. The pharmaceutical composition of claim 113where R_(C) is: (V) —(CR_(C−x)R_(C−y))₀₋₄—R_(C-aryl) where R_(C-aryl) isphenyl.
 131. The pharmaceutical composition of claim 113 where phenylsubstituted in the 3 -position or 3,5-positions.
 132. The pharmaceuticalcomposition of claim 113 where R_(C) is: (VI) —CH₂—R_(C-heteroaryl),133. The pharmaceutical composition of claim 113 where R_(C) is: (VII)—CH₂—R_(C-heterocycle).
 134. The pharmaceutical composition of claim 113where R_(C) is: (X) -cyclohexyl ring fused to a phenyl ring.
 135. Thepharmaceutical composition of claim 113 where R_(C) is: (I)-(C₁-C₁₀)alkyl-K₁₋₃ where each K is: (1) H, (11) carboxyl, (16) aminounsubstituted or substituted with C₁-C₆ alkyl; or (18) carboxyl methylester; (II) —(CH₂)₀₋₃-J-[-K]₁₋₃, where J is: (A) a 5 to 7 atommonocyclic aryl group, or (B) a 5 to 10 atom multicyclic cycloalkylgroup, and each K is: (1) H, (3) C₁-C₃ alkoxy, or (11) carboxyl, (III)—(CH₂)₀₋₃-(C₃-C₇) cycloalkyl where cycloalkyl can be unsubstituted orsubstituted with one, two or three: (B) —CO—OH, (C) —CO—O—(C₁-C₄ alkyl),or (E) C₁-C₆ alkoxy, (IV) —(CH₂)₂₋₆—OH, (V) —(CH₂)₀₋₄—R_(C-aryl), (VI)—(CH₂)₀₋₄—R_(C-heteroaryl), (VII) —(CH₂)₀₋₄—R_(C-heterocycle), or(XVIII) —(C₂-C₈) alkynyl.
 136. The pharmaceutical composition of claim113 where R_(C) is: (I) —(C₁-C₁₀)alkyl-K where K is H, carboxyl,carboxyl methyl ester, amino unsubstituted or substituted with C₁-C₆alkyl, (II) a benzyl or phenylpropyl group substituted with a carboxylgroup, (III) —(CH₂)₀₋₃-(C₃-C₇) cycloalkyl where cycloalkyl iscyclohexyl, cyclohexyl substituted with 1 or 2 carboxyl groups, orcyclohexyl substituted with 1 or 2 alkoxy groups, (V) —(CH₂)₀₋₄-phenylsubstituted or unsubstituted with F, (VI) —(CH₂)₀₋₄-heteroaryl, or (VII)selected from —(CH₂)₀₋₄-morpholinyl and —(CH₂)₀₋₄-tetrahydrofuryl. 137.The pharmaceutical composition of claim 113 where R_(C) is: (I) C₅H₁₀-Kor C₇H₁₄-K where K is carboxyl or carboxyl methyl ester, (II) a benzylor phenylpropyl group substituted with a carboxyl group at the5-position, or (III) a cyclohexyl ring substituted at the 3- and 5-positions or at the 4-position with a carboxyl group.
 138. Thepharmaceutical composition of claim 113 where R₁ is: (I) C₁-C₅ alkyl,(II) —(CH₂)₁₋₂—S—CH₃, (IV) C₁-C₅ alkenyl, (V) —(CH₂)₀₋₃-(R_(1-aryl))where R_(1-aryl) is as defined above, and (VI)—(CH₂)₀₋₃-(R_(1-heteroaryl) where R) _(1-heteroary) is as defined above,wherein any of the above are unsubstituted or substituted with up to twoC₁-C₃ alkyl, —F, —Cl, —Br, —I, or —CF₃; where R₂ is: (I) —H (II) C₁-C₆alkyl, or (III) —(CH₂)₀₋₃-R₂, where R₂, is (C₃-C₆)cycloalkyl, R_(1-aryl)or R_(1-heteroaryl) where R₁ aryl is a 5 or 6-membered aryl group andR_(1-heteroaryl) is as defined above; where R_(N) is: (II) A—X_(N)-where X_(N) is —CO—, wherein A is (A) —T-E—(Q)_(m′), (1) where —T is

where (a) x=1 when y=1 and x=2 when y=0, (b) m is 0, 1, 2 or 3, (c) thevalues of x and y vary independently on each carbon when m is 2 and 3,and (d) R′″ varies independently on each carbon and is H, (C₁-C₂) alkyl,phenyl, or phenyl(C₁-C₃)alkyl; (2) -E is (a) C₁-C₅ alkyl, but only if m′does not equal 0, (b) methylthioxy(C₂-C₄)alkyl, (c) an aryl group having5 to 7 atoms when monocyclic or having 8 to 12 atoms when fused, (d) aheterocyclic group having 5 to 7 atoms when monocyclic or having 8 to 12atoms when fused, (e) a mono or fused ring cycloalkyl group having 5 to10 carbon atoms, (f) biphenyl, (g) diphenyl ether, (h) diphenylketone,(i) phenyl(C₁-C₈)alkyloxyphenyl, or (j) C₁-C₆ alkoxy; (3) —Q is (a)C₁-C₃ alkyl, (b) C₁-C₃ alkoxy, (c) C₁-C₃ alkylthioxy, (d) C₁-C₆alkylacylamino, (e) C₁-C₆ alkylacyloxy, (f) amido (including primary,C₁-C₆ alkyl and phenyl secondary and tertiary amino moieties), (g) C₁-C₆alkylamino (h) phenylamino, (i) carbamyl (including C₁-C₆ alkyl andphenyl amides and esters), (j) carboxyl (including C₁-C₆ alkyl andphenyl esters), (k) carboxy(C₂-C₅)alkoxy, (l) carboxy(C₂-C₅)alkylthioxy,(m) heterocyclylacyl, (n) heteroarylacyl, or (o) hydroxyl; (4) m′ is 0,1, 2 or 3; (B) -E(Q)m_(″) wherein E and —Q are as defined as above andm″ is 0, 1, 2, or 3; (C) —T-E wherein -E and —Q are as defined as above;or (D) -E wherein -E is as defined as above; where R_(C) is: (I)—(C₁-C₁₀)alkyl-K₁₋₃ (E) the alkyl chain optionally contains acombination of up to three atoms of oxygen and sulfur each such atomreplacing one carbon, (F) each K is: (2) C₁-C₃ alkyl, (3) C₁-C₃ alkoxy,(4) C₁-C₃ alkylthioxy, (5) C₁-C₆ alkylacylamino, (6) C₁-C₆ alkylacyloxy,(7) amido, (8) C₁-C₆ alkylamino (9) phenylamino, (10) carbamyl, (11)carboxyl, (12) carboxy(C₂-C₅)alkoxy, (13) carboxy(C₂-C₅)alkylthioxy,(14) heterocyclylacyl, (15) heteroarylacyl, (16) amino unsubstituted orsubstituted with C₁-C₆ alkyl, (17) hydroxyl, or (18) carboxyl methylester; (II) —(CH₂)₀₋₃-J-[(-(CH₂)₀₋₃-K]₁₋₃ where K is: (2) C₁-C₃ alkyl,(3) C₁-C₃ alkoxy, (4) C₁-C₃ alkylthioxy, (5) C₁-C₆ alkylacylamino, (6)C₁-C₆ alkylacyloxy, (7) amido, (8) C₁-C₆ alkylamino (9) phenylamino,(10) carbamyl, (11) carboxyl, (12) carboxy(C₂-C₅)alkoxy, (13)carboxy(C₂-C₅)alkylthioxy, (14) heterocyclylacyl, (15) heteroarylacyl,(16) amino unsubstituted or substituted with C₁-C₆ alkyl, (17) hydroxyl,or (18) carboxyl methyl ester; J is: (A) a 5 to 7 atom monocyclic arylgroup, (B) a 8 to 12 atom multicyclic aryl group, (C) a 5 to 7 atommonocyclic heterocyclic group, (D) a 8 to 12 atom multicyclicheterocyclic group, or (E) a 5 to 10 atom monocyclic or multicycliccycloalkyl group; and where B is O or NH.
 139. The pharmaceuticalcomposition of claim 113 where the pharmaceutically acceptable salt is asalt of hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric,phosphoric, citric, methanesulfonic, CH₃—(CH₂)_(n)—COOH where n is 0thru 4, HOOC—(CH₂)_(n)—COOH where n is as defined above, HOOC—CH═CH—COOHand φ—COOH acid or triethanolamine, N-methylglucamine, diethanolamine,ethanolamine, tris(hydroxymethyl)aminomethane (TRIS), ammonia, orcarbonate, bicarbonate, phosphonate, or hydroxide salts of an alkali oralkaline earth metal.
 140. The pharmaceutical composition of claim 113wherein said compound is: N-[(1S, 2S, 4R)-1-(3,5-Difluorobenzyl)-4-(syn,syn)-(3,5-dimethoxycyclohexylcarbamoyl)-2-hydroxyhexyl]-N,N-dipropylisophathalamide,6-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-hexanoicacid,5-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S-hydroxyhexanoylamino]-pentanoicacid,4-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-butyricacid,3-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-propionicacid, 8-[6-(3,5-Difluorophenyl)-5-(S)-(3-dipropylcarbamoylbenzoylamino)-2-(R)-ethyl-4-(S)-hydroxyhexanoylamino]-octanoicacid,8-[6-(3,5-Difluoro-phenyl)-5-(6)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-octanoicacid methyl ester, N-[4-(R)-Butylcarbamoyl- 1-(5)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-hexyl]-N,N-dipropyl-isophthalamide,N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[4-(R)-(Cyclohexylmethyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(piperidine-1-carbonyl)-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(2-dimethylamino-ethylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[4-(R)-(Butyl-methyl-carbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(3-hydroxy-propylcarbamoyl)-hexyl]-N,N-dipropyl-isophthalamide,4-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid methyl ester,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(3-dimethylamino-propylcarbamoyl)-2-(S)-hydroxy-hexyl]-N,N-dipropyl-isophthalamide,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid, 4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-methyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-2-(R)-propyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxyl-2-(R)-isobutyl-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid, 4-(anti)-([2-(R)-Benzyl-6-(3,5-difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-benzoylamino)-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid,4-(anti)-([6-(3,5-Difluoro-phenyl)-5-(S)-(3-dipropylcarbamoyl-5-methyl-benzoylamino)-2-(R)-ethyl-4-(S)-hydroxy-hexanoylamino]-methyl)-cyclohexanecarboxylicacid methyl ester,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(2-morpholin-4-yl-ethylcarbamoyl)-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-isobutylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[4-(R)-(2-Diethylamino-ethylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-pentyl)-5-methyl-N,N-dipropyl-isophthalamide,N-[4-(R)-(Adamantan-2-ylcarbamoyl)-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-methyl-5-morpholin-4-yl-5-oxo-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[4-(R)-Benzylcarbamoyl-1-(S)-(3,5-difluoro-benzyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-(4-fluoro-benzylcarbamoyl)-2-(S)-hydroxy-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-phenethylcarbamoyl-pentyl]-5-methyl-N,N-dipropyl-isophthalamide,N-[1-(S)-(3,5-Difluoro-benzyl)-4-(R)-[(furan-2-ylmethyl)-carbamoyl]-2-(S)-hydroxy-pentyl)-5-methyl-N,N-dipropyl-isophthalamide, or N-[1-(S)-(3,5-Difluoro-benzyl)-2-(S)-hydroxy-4-(R)-(prop-2-ynylcarbamoyl)-pentyl]-5-methy-N,N-dipropyl-isophthalamide.141. The pharmaceutical composition of claim 113 wherein said compoundis: